DISLIPEMIASDISLIPEMIAS

UN FACTOR DE RIESGO UN FACTOR DE RIESGO SIEMPRE VIGENTESIEMPRE VIGENTE

Dr Marcos BaroniDr Marcos Baroni

Dpto de Prevención Dpto de Prevención CardiovascularCardiovascular (Instituto Modelo de Cardiología – (Instituto Modelo de Cardiología – Córdoba)Córdoba)

Risk Risk FactorsFactors

ContControl rol (%) (%)

Cases Cases (%)(%)

OR (99% OR (99% CI)CI)Adjusted Adjusted forforAge, Sex,Age, Sex,and and SmokingSmoking

OR (99% OR (99% CI)CI)Adjusted Adjusted forforAll OtherAll OtherRisk Risk FactorsFactors

Apo B/ Apo Apo B/ Apo AA

2020 33.533.5 3.873.87 (3.39 - (3.39 -4.42)4.42)

3.253.25 (2.82 – (2.82 – 3.76)3.76)

Current Current smokingsmoking

26.826.8 45.245.2 2.952.95 (2.72 -(2.72 -3.20)3.20)

2.872.87 (2.58-(2.58-3.19)3.19)

DiabetesDiabetes 7.57.5 18.518.5 3.083.08 (2.77-(2.77-3.72)3.72)

2.372.37 (2.07-(2.07-

2.71)2.71) HypertensioHypertensionn

21.921.9 39.0 39.0 2.482.48 (2.30-(2.30-2.68) 2.68)

1.911.91 (1.74-(1.74-2.10) 2.10)

Abdominal Abdominal obesity (3 vs obesity (3 vs 1)†1)†

33.333.3 46.346.3 2.222.22 (2.03-(2.03-2.42)2.42)

1.62 1.62 (1.45-(1.45-1.80)1.80)

Lancet. 2004;364:937-952 Lancet. 2004;364:937-952

INTERHEARTINTERHEART : Risk of AMI Associated With : Risk of AMI Associated With Risk Factors Risk Factors

LDL cholesterolLDL cholesterol Strongly associated with atherosclerosis and CVD eventsStrongly associated with atherosclerosis and CVD events 10% increase results in an approximate 20% increase in 10% increase results in an approximate 20% increase in

CHD risk CHD risk Most of the cholesterol in plasma is found in LDL Most of the cholesterol in plasma is found in LDL

particlesparticles Smaller denser LDL are more atherogenic than larger, Smaller denser LDL are more atherogenic than larger,

less dense particlesless dense particles Risk associated with LDL-C is increased by other risk Risk associated with LDL-C is increased by other risk

factors:low HDLfactors:low HDL

smokingsmoking hypertensionhypertension diabetesdiabetes

                          Incidence of recurrent MI

                                                                                         

                                   

                             

                          Incidence of recurrent MI

HDL cholesterolHDL cholesterol HDL-C has a protective effect for risk of HDL-C has a protective effect for risk of

atherosclerosis and CHDatherosclerosis and CHD

Epidemiological studies show the lower the HDL-C Epidemiological studies show the lower the HDL-C level, the higher the risk for atherosclerosis and level, the higher the risk for atherosclerosis and CHDCHD low level (<40 mg/dL, 1 mmol/L) increases risklow level (<40 mg/dL, 1 mmol/L) increases risk

HDL-C tends to be low when triglycerides are highHDL-C tends to be low when triglycerides are high

HDL-C is lowered by smoking, obesity and HDL-C is lowered by smoking, obesity and physical inactivityphysical inactivity

Rol de la apolipoproteínas Rol de la apolipoproteínas de las HDL en la remoción de las HDL en la remoción

de las LDL oxidadasde las LDL oxidadas Transferencia CETP de las LDL Transferencia CETP de las LDL

oxidada a las HDLoxidada a las HDL

Las LDL oxidadas son reducidas por Las LDL oxidadas son reducidas por las apolipoproteínas de las HDLlas apolipoproteínas de las HDL

Hígado capta los lípidos reducidos Hígado capta los lípidos reducidos por las HDL más rápidamente que por las HDL más rápidamente que las LDLlas LDL

Low HDL-C is an IndependentLow HDL-C is an IndependentPredictor of CHD Risk even when Predictor of CHD Risk even when

LDL-C is LowLDL-C is Low

0

1

2

3

Ris

k o

f C

HD

100 mg/l

160 mg/l 220 mg/l HDL-C85 mg/l

65

25

COLESTEROL HDLCOLESTEROL HDL

Factores Modificadores Factores Modificadores de las HDLde las HDL

Efectos AntiinflamatoriosEfectos Antiinflamatorios::

1.1. Apo A1 mimetizadaApo A1 mimetizada2.2. EjercicioEjercicio3.3. Dieta baja en grasasDieta baja en grasas4.4. Grasas PoliinsaturadasGrasas Poliinsaturadas5.5. EstatinasEstatinas

Factores Modificadores Factores Modificadores de las HDLde las HDL

Efectos Proinflamatorios:Efectos Proinflamatorios:1.1. Ateroesclerosis coronariaAteroesclerosis coronaria2.2. DBTDBT3.3. HemodiálisisHemodiálisis4.4. Grasas saturadasGrasas saturadas5.5. InfeccionesInfecciones6.6. Artritis ReumatoideaArtritis Reumatoidea7.7. CirugíasCirugías8.8. LESLES

¿Por Qué Pro ¿Por Qué Pro inflamatorias?inflamatorias?

Disminución Apo A1Disminución Apo A1

Daño de Apo A1 por la Daño de Apo A1 por la mieloperoxidasamieloperoxidasa

Inflamación asociada a estrés Inflamación asociada a estrés oxidativooxidativo (puede llevar a la alteración y reducción (puede llevar a la alteración y reducción

de las enzimas antioxidantes)de las enzimas antioxidantes)

Nuevos Tests evaluando Nuevos Tests evaluando función HDLfunción HDL

Determinación Quimiotaxis de Determinación Quimiotaxis de MonocitosMonocitos

Moléculas de AdhesiónMoléculas de Adhesión

Estimulación por el CobreEstimulación por el Cobre

( todos en fase experimental)( todos en fase experimental)

                                                                                         

                                   

                             

CETPCETP

HDL (mg/dl) 3 meses HDL (mg/dl) 3 meses TorcetrabipTorcetrabip

Radio para Radio para muerte CVmuerte CV

< 60< 60 1.001.00

60 - 7060 - 70 0.670.67

71 - 8071 - 80 0.470.47

81 - 9381 - 93 0.570.57

> 93> 93 0.430.43

ILLUMINATE: Major ILLUMINATE: Major resultsresults

N Engl J Med N Engl J Med 2007;356:1304-1316 2007;356:1304-1316

ILLUMINATE: Major resultsILLUMINATE: Major results

End End point point

AtorvastatAtorvastatinin

(n: 7534)(n: 7534)

Atorvatatin Atorvatatin ++

TorcetrabiTorcetrabipp

(n:7533)(n:7533)

Hazard Hazard RatioRatio

(95 % CI)(95 % CI)

PP

EventEventos os

MayorMayoreses

373373 464464 1.251.25 (1.09- 1.44) (1.09- 1.44)

0.0010.001

MuertMuerteses

5959

9393

1.581.58(1.14 – 2.19)(1.14 – 2.19)

0.0060.006

N Engl J Med N Engl J Med 2007;356:1304-1316 2007;356:1304-1316

Riesgo de EC segun Riesgo de EC segun TrigliceridosTrigliceridos

( Framingham Heart Study)( Framingham Heart Study)

0

0.5

1

1.5

2

2.5

3

50 100 150 200 250 300 350 400

Men Women

N=5127

Hipertrigliceridemia + HDL Hipertrigliceridemia + HDL bajobajo

Hipertrigliceridemia + HDL Hipertrigliceridemia + HDL bajobajo

Es usual en síndrome metabólicoEs usual en síndrome metabólico Es un patrón muy común en Es un patrón muy común en

aterosclerosis tempranaaterosclerosis temprana Asociada a la tríada de ↑ILDL y Asociada a la tríada de ↑ILDL y

VLDL con LDL pequeña-densaVLDL con LDL pequeña-densa Tríada lipídica = dislipidemia Tríada lipídica = dislipidemia

aterogénicaaterogénica

TRIGLICERIDOS POSPRANDIALES: FACTOR DE RIESGO CV

La trigliceridemia posprandial (2 hs.)es un FR independiente para aterosclerosis temprana

La trigliceridemia posprandial (2 hs.)es un FR independiente para aterosclerosis temprana

Enfermedad coronaria

Enfermedad carotídea (IMT)

Enfermedad coronaria

Enfermedad carotídea (IMT)

Boquist S et al. Circulation 17:723,1999Boquist S et al. Circulation 17:723,1999

•Aumento de triglicéridos posprandiales causan disfunción endotelial.

•El bloqueo del SRA (IECA y Ant. At1) previenen esta disfunción

•Aumento de triglicéridos posprandiales causan disfunción endotelial.

•El bloqueo del SRA (IECA y Ant. At1) previenen esta disfunción

Wilmink HW et al. JACC 34:140,1999

TRIGLICÉRIDOS Y GLUCOSA POST TRIGLICÉRIDOS Y GLUCOSA POST PRANDIALESPRANDIALES

Dislipemia en el Dislipemia en el Síndrome MetabólicoSíndrome Metabólico

Hipertrigliceridemia por Hipertrigliceridemia por sobreproducción de VLDLsobreproducción de VLDL

Disminución de las HDLDisminución de las HDL

Cambios cualitativos de las LDLCambios cualitativos de las LDL

COLESTEROL NO HDLCOLESTEROL NO HDL

COLESTEROL NO HDLCOLESTEROL NO HDL = = COL TOTAL – COL TOTAL – COL HDLCOL HDL

Therapeutic Targets for Low-Density Lipoprotein (LDL) Cholesterol and Non-High-Density

Lipoprotein (non-HDL) Cholesterol as Recommended by the National Cholesterol

Education Program Adult Treatment Panel IIIRisk Level Risk Level LDL LDL

Cholesterol Cholesterol Goal Goal

Non-HDL Non-HDL Cholesterol Cholesterol Goal Goal

CHD and CHD risk CHD and CHD risk equivalents* equivalents*

<100 mg/dL <100 mg/dL <130 <130 mg/dL mg/dL

Multiple (2+) risk Multiple (2+) risk factors (10-year factors (10-year CHD risk </=20%) CHD risk </=20%)

<130 mg/dL <130 mg/dL <160 <160 mg/dL mg/dL

0-1 Risk factor0-1 Risk factor <160 mg/dL <160 mg/dL <190 <190 mg/dL mg/dL

Effect of lipid-modifying Effect of lipid-modifying

therapies on lipidstherapies on lipids Therapy

Bile acidsequestrants

Nicotinic acid

Fibrates

Probucol

Statins*

Ezetimibe

TC

Down 20%

Down 25%

Down 15%

Down 25%

Down 19–37%

-

LDL

Down 15–30%

Down 25%

Down 5–15%

Down 10–15%

Down 25–50%

Down18%

HDL

Up 3–5%

Up 15–30%

Up 20%

Down20–30%

Up 4–12%

Up1%

TG

Neutral or up

Down 20–50%

Down 20–50%

Neutral

Down 14-29%

Down 8%

Patienttolerability

Poor

Poor toreasonable

Good

Reasonable

Good

Good

TC–total cholesterol, LDL–low density lipoprotein, HDL–high density lipoprotein, TG–triglyceride. *Daily dose of 40 mg of atorvastatin, simvastatin, pravastatin and fluvastatin.

Yeshurun D, Gotto AM. Southern Med J 1995;88(4):379–391. Knopp RH. N Engl J Med 1999;341:498–511. Product Prescribing Information. Gupta EK, Ito MK. Heart Dis 2002;4:399-409.

,

NCEP ATP III: LDL-C Goal NCEP ATP III: LDL-C Goal (2004 proposed (2004 proposed

modifications)modifications) High Risk

CHD or CHD risk equivalents

(10-yr risk >20%)

LD

L-C

level

100 -

160 -

130 -

190 -

Lower Risk

< 2 risk factors

Moderately High Risk

≥ 2 risk factors

(10-yr risk 10-20%)

goal

160mg/dL

goal

130mg/dL

70 -

goal

100 mg/dL

or optional

70 mg/dL*

Moderate Risk

≥ 2 risk factors

(10-yr risk <10%)

goal

130 mg/dL

or optional

100 mg/dL*

*Therapeutic option

70 mg/dL =1.8 mmol/L; 100 mg/dL = 2.6 mmol/L; 130 mg/dL = 3.4 mmol/L; 160 mg/dL = 4.1 mmol/L

Grundy SM et al. Circulation 2004;110:227-239.

Existing LDL-C goals

Proposed LDL-C goals

ESTATINASESTATINAS

↓ ↓

↓ ↓ HMG CoA reductasaHMG CoA reductasa

↓ ↓

↓ ↓Niveles intrahepatocitarios de Niveles intrahepatocitarios de colesterolcolesterol

↓ ↓

↑ ↑ Expresión del receptor de Expresión del receptor de LDLLDL

↓ ↓

↓ ↓LDL circulante LDL circulante

↓ ↓

↓ ↓ Colesterol PlasmáticoColesterol Plasmático

Efecto Efecto AdversoAdverso

EfectoEfecto

GeneralGeneral Pérdida de apetito, pérdida de Pérdida de apetito, pérdida de pesopeso

PielPiel Rásh cutáneoRásh cutáneo

Sistema Sistema NerviosoNervioso

Pérdida de concentración, cefaleaPérdida de concentración, cefalea

GastrointestiGastrointestinalnal

Dolor abdominal, naúseas, Dolor abdominal, naúseas, diarreadiarrea

HígadoHígado Hepatitis, aumento de Hepatitis, aumento de transaminasastransaminasas

MúsculosMúsculos Dolor muscular, ↑ CPKDolor muscular, ↑ CPK , miositis, , miositis, rabdomiólisisrabdomiólisis

Sistema Sistema InmuneInmune

Síndrome simil lupusSíndrome simil lupus

Unión Unión ProteicaProteica

Disminución de unión a proteínas Disminución de unión a proteínas de warfarinade warfarina

Is Lower Better? Is Lower Better? Relationship between LDL-C and CV Relationship between LDL-C and CV

Event RateEvent Rate

                                                                                         

                                   

                             

                          Cholesterol balance

Is Lower Better? Is Lower Better? Relationship between LDL-C and CV Relationship between LDL-C and CV

Event RateEvent Rate

LDL-C achieved mg/dL (mmol/L)

WOSCOPS - Pl

AFCAPS/TexCAPS - Pl

ASCOT - PlAFCAPS/TexCAPS - Rx

WOSCOPS - Rx

ASCOT - Rx

ALLHAT - RxALLHAT - Pl

4S - Rx

HPS - Pl

LIPID - Rx

4S - Pl

CARE - Rx

LIPID - Pl

PROSPER - PlCARE - Pl

HPS - Rx

PROSPER - Rx

0

5

10

15

20

25

30

70(1.8) 90(2.3) 110(2.8) 130(3.4) 150(3.9) 170(4.4) 190(5.0) 210(5.4)

Event rate %

- Secondary Prevention

- Primary Prevention

Rx - Statin therapy

Pl - Placebo

Ballantyne CM et al. Am J Cardiol 1998;82:3Q–12Q.

The Anglo-Scandinavian Cardiac Outcomes The Anglo-Scandinavian Cardiac Outcomes Trial Lipid Lowering Arm: Extended Trial Lipid Lowering Arm: Extended Observations 2 Years After TrialObservations 2 Years After Trial

Eur Heart J.  2008;29(4):499-Eur Heart J.  2008;29(4):499-

508.  ©2008508.  ©2008  

¿Qué Podemos Hacer con ¿Qué Podemos Hacer con las HDL?las HDL?

Considerar que los pacientes con Considerar que los pacientes con disminución de HDL tienen riesgo disminución de HDL tienen riesgo incrementado para enfermedad incrementado para enfermedad cardiovascularcardiovascular

Conocer que las enfermedades crónicas Conocer que las enfermedades crónicas alteran la calidad de las HDL alteran la calidad de las HDL (proinflamatorias) aumentando el riesgo (proinflamatorias) aumentando el riesgo CV (a pesar de valores elevados de HDL)CV (a pesar de valores elevados de HDL)

El uso de estatinas, fibratos, niacinas y El uso de estatinas, fibratos, niacinas y medidas no farmacológicas pueden medidas no farmacológicas pueden reducir el riesgo CVreducir el riesgo CV

Anacetrapib ???Anacetrapib ???

FIBRATOSFIBRATOS

Modo de AcciónModo de Acción ↑ ↑ actividad de lipoprotein lipasa (lipolisis actividad de lipoprotein lipasa (lipolisis

de trigliceridos, ↑ clearance)de trigliceridos, ↑ clearance) ↓ ↓ lipolisis en el tejido adiposo, ↓ lipolisis en el tejido adiposo, ↓

liberación AGLliberación AGL ↓ ↓ secrecion de VLDL por el hígadosecrecion de VLDL por el hígado ↓ ↓ captación de AGL por el hígadocaptación de AGL por el hígado ↑ ↑ HDL moderadamenteHDL moderadamente

– – Efectos AdversosEfectos Adversos Cálculos Biliares (disconfort epigástrico, Cálculos Biliares (disconfort epigástrico,

intolerancia a CCK, meteorismo)intolerancia a CCK, meteorismo) Usar con precaución en ptes c/ patolog Usar con precaución en ptes c/ patolog

biliar, mujeres, obesosbiliar, mujeres, obesos Miopatia (injuria muscular)Miopatia (injuria muscular)

Debilidad, o dolor muscular inusualDebilidad, o dolor muscular inusual Puede aumentar risgo de miopatia inducida Puede aumentar risgo de miopatia inducida

por estatinas cuando se usan por estatinas cuando se usan conjuntamente (rabdomiolisis ha ocurrido conjuntamente (rabdomiolisis ha ocurrido raramente)raramente)

Desplaza warfarina y ciclosporina de la Desplaza warfarina y ciclosporina de la albúminaalbúmina

plasmática. Necesidad de disminuir dosis plasmática. Necesidad de disminuir dosis de warfarina. Chequear RIN:de warfarina. Chequear RIN:

FIBRATOSFIBRATOS

TERAPEÚTICA INSUFICIENTE TERAPEÚTICA INSUFICIENTE ????

Marine fish oil rich in omega 3 fatty acids lower trigliceride Marine fish oil rich in omega 3 fatty acids lower trigliceride levels and may be effective in combination with statins to levels and may be effective in combination with statins to treat patients with combined hyperlipidemiatreat patients with combined hyperlipidemia

Fish oils plus statin may often be an alternative to fibrate Fish oils plus statin may often be an alternative to fibrate plus statinplus statin

Fish oils may have other cardiovascular effects Fish oils may have other cardiovascular effects complementary to those of statins, such as:complementary to those of statins, such as:

- Reduction in malignant ventricular dysrithmias- Reduction in malignant ventricular dysrithmias - Antithrombotic effects- Antithrombotic effects - Improved endothelial reactivity /relaxation- Improved endothelial reactivity /relaxation - Antiinflammatory effects- Antiinflammatory effects Bays HE et al – Expert Opin Pharmacother 2003 -4 -1901 -1938Bays HE et al – Expert Opin Pharmacother 2003 -4 -1901 -1938Kris Etherton – Circulation 2002 – 106 -2747 - 2757Kris Etherton – Circulation 2002 – 106 -2747 - 2757

FISH OILS AND STATINSFISH OILS AND STATINS

Statins are commonly used to reduce CHD risk in patients Statins are commonly used to reduce CHD risk in patients with type 2 diabetes and the metabolic syndromewith type 2 diabetes and the metabolic syndrome

PPAR y agonist, improved glucose control and may have lipid PPAR y agonist, improved glucose control and may have lipid effects complementary to those of statinseffects complementary to those of statins

LDL particle size may be increased with PPAR yLDL particle size may be increased with PPAR y

Trigliceride levels are decreased with PPAR yTrigliceride levels are decreased with PPAR y HDL are increased with PPAR yHDL are increased with PPAR y The metabolic effects of PPAR y agonist may be complementary to The metabolic effects of PPAR y agonist may be complementary to

the lipid effects of statins in patients with type 2 diabetes and the lipid effects of statins in patients with type 2 diabetes and metabolic syndromemetabolic syndrome

Bays HE- Brithis Journal of Diabetes Bays HE- Brithis Journal of Diabetes and Vascular Disease 2003 -3 356-360and Vascular Disease 2003 -3 356-360

insberg HN –Am J of Cardiol 2003 – 91 : 29E-39Einsberg HN –Am J of Cardiol 2003 – 91 : 29E-39E

PPAR- y AGONIST AND PPAR- y AGONIST AND STATINSSTATINS

Benefits of Intensive Lifestyle Benefits of Intensive Lifestyle Changes on TG LevelsChanges on TG Levels

Within DPP, Within DPP, TG levels fell TG levels fell significantly more significantly more in the group with in the group with intensive lifestyle intensive lifestyle intervention than in intervention than in the metformin groupthe metformin group

Aimed to reduce Aimed to reduce weight by 7% with weight by 7% with a low-fat dieta low-fat diet

150 minutes of 150 minutes of moderate exercise moderate exercise per weekper week

180

160

140

120

160160

140

100

Lifestyle

TG

(m

g/d

L)

Benefits of Intensive Lifestyle Benefits of Intensive Lifestyle Changes on TG LevelsChanges on TG Levels

Benefits of Intensive Lifestyle Benefits of Intensive Lifestyle Changes on TG LevelsChanges on TG Levels

Within DPP, Within DPP, TG levels fell TG levels fell significantly more significantly more in the group with in the group with intensive lifestyle intensive lifestyle intervention than in intervention than in the metformin groupthe metformin group

Aimed to reduce Aimed to reduce weight by 7% with weight by 7% with a low-fat dieta low-fat diet

150 minutes of 150 minutes of moderate exercise moderate exercise per weekper week

Lifestyle

180

160

140

120

100

TG

(m

g/d

L)

BaselineYear 1Year 2Year 3

DPP=Diabetes Prevention Program.

National Institute of Diabetes & Digestive & Kidney Diseases of the NIH. Accessed at http://www.niddk.nih.gov/welcome/releases/8_8_01.htm.

Ratner R et al. Diabetes Care. 2005;28:888-894.

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