Adult Treatment Panel III (ATP III) Guidelines May 2001 Ipercolesterolemie famigliari Ipercolesterolemie e rischio cardio vascolare globale

Chilomicroni (apo B-48, C, E) MACROFAGO VLDL Apo B-100 Apo C, E IDL LDL Apo B-100 HDL3 Apo AI-II HDL2 TG Fatty Acids COL trasporto inverso Site of Synthesis of Lipoproteins

CM VLDL IDL LDL HDL Lipoprotein Nomenclature and Composition Major apoB apoB apoB apoB apoA-I Protein Major TGTG CE CE CE Lipid CM= chylomicronTG=triglyceride VLDL= very low density lipoproteinCE= cholesteryl ester IDL= intermediate density lipoprotein LDL= low density lipoprotein HDL= high density lipoprotein Apo = apolipoprotein

Iperlipoproteinemie secondo Fredrikson Classificazione fenotipica VChilomicroni, VLDLTG & Col IVVLDLTG & Col IIIIDL, VLDL, ChilomicroniCol & TG (1/1) IIbLDL & VLDLCol & TG IIaLDLCol IChilomicroniTG

Iperlipoproteinemie genetiche Ipercol FamIV o V2-3/1000AD? IperlipidemiaIIb o IV3-5/1000AD? Familiare Combinata FHIIa o IIb1/500ADdef recettore LDL FDAIIa1/500ADApo B100 def PoligenicaIIa??? DisßIII?ARApo E2E2 IperchiloI o Vrara +ARDeficit LPL/Apo C-II Iper Col > Iper TG Iper TG > Iper Col

Diagnosi iperlipoproteinemie genetiche - Criteri clinici - Famigliarità per ipercolesterolemia (parenti di I grado) Famigliarità per CVD < 55 anni (parenti di I grado) Xantomi tendinei LDL cut off ?? LDL mg/dl ?? Apo B cut off

Adult Treatment Panel III (ATP III) Guidelines May 2001 National Cholesterol Education Program

ATP I & ATP II MAJOR GOAL OF THERAPY LDL-CHOLESTEROL MAJOR TARGETS OF THERAPY FH Het & Hom FDA apo B-100 PH

T2DM/T1DM Ipotiroidismo Cushing IRC Sindrome Nefrosica Colestasi Obesità Iperlipemia iatrogena Alcohol High-CARBO Diet Estrogeni Ticlopidina Diuretici ß-block Glucocorticoidi Iperlipoproteinemie secondarie

New Features of ATP III Multiple metabolic risk factors (metabolic syndrome) Focus on Multiple Risk Factors Diabetes: CHD risk equivalent Framingham projections of 10-year CHD risk

Diabete e CVD rischio relativo no DM no IMA no DM IMA DM no IMA DM IMA Mukamal KJ et al Diabetes Care 24; 1422, 2001 rischio relativo di mortalità CVD

NEFA Il paradigma dellaumentato flusso dei NEFA Perseghin G. et al. Curr Opin Lipidol, 2005 Dieta Sedentarietà Geni

Eccesso di grasso viscerale e dislipidemia Pouliot MC et al. Diabetes 1992;41: mg/dL Trigliceridi Magri Colesterolo HDL Grasso viscerale (soggetti obesi) BassoAlto Magri Grasso viscerale (soggetti obesi) BassoAlto

Leccesso di grasso viscerale promuove un fenotipo aterogeno Elevati trigliceridi, basso C-HDL e elevate particelle piccole e dense di C-LDL C-LDL normale LDL d ense TG C-HDL TG C-HDL Magri grasso viscerale Rischio CHD Despres JP. Ann Med 2001;33:534-41

Fattori di Rischio Cardiovascolare

Rischio Cardiovascolare Globale

UKPDS BMJ 316; 823, 1998 Diabete e CVD PRIORITA

pazienti con eventi vascolari (%) Placebo SIMVA HPS Lancet 360; 7, 2002 Terapia farmacologica EFFICACIA delle STATINE

Modulazione dellintervento

LDL Cholesterol Goals and Cutpoints for Therapeutic Lifestyle Changes (TLC) and Drug Therapy in Different Risk Categories 190 (160–189: LDL- lowering drug optional) 160 <1600–1 Risk Factor 10-year risk 10–20%: year risk <10%: < Risk Factors (10-year risk 20%) 130 (100–129: drug optional) 100 <100 CHD or CHD Risk Equivalents (10-year risk >20%) LDL Level at Which to Consider Drug Therapy (mg/dL) LDL Level at Which to Initiate Therapeutic Lifestyle Changes (TLC) (mg/dL) LDL Goal (mg/dL)Risk Category

Terapia farmacologica EFFICACIA delle STATINE Colesterolo totale20-40% LDL-C30-50% Trigliceridi5-20% HDL-C5% Terapia farmacologica EFFETTI PLEIOTROPICI delle STATINE Infiammazione Funzione endoteliale Stabilità di placca

Drug Therapy HMG CoA Reductase Inhibitors (Statins) Major side effects –Myopathy (CK) –Increased liver enzymes (AST, ALT) Contraindications –Absolute: liver disease –Relative: use with certain drugs Fibrati (assoluta controindicazione ad associazione con gemfibrozil, mentre la più tollerata è con fenofibrato), immunosoppressori (CyA), ketoconazolo –Citocromo P450 (macrolidi, chinolonici)

Terapia farmacologica quale statina? The Curves Study atorva simva lova prava fluva Jones P et al Am J Cardiol 81: 582, 1998 rosuva

PravaSimvaFluvaAtorva/Rosuva Emivita CYP 450 Int Warfarin Int Digitale Lipofilia 2h3h3h15h noyesyesyes yesyesnoyes noyesyesyes noyes no yes Drugs Features

Drug Therapy Bile Acid Sequestrants Major actions –Reduce LDL-C 15–30% –Raise HDL-C 3–5% –May increase TG Side effects –GI distress/constipation –Decreased absorption of other drugs Contraindications –Dysbetalipoproteinemia –Raised TG (especially >400 mg/dL)

Bile Acid Sequestrants DrugDose Cholestyramine4–16 g

Bile Acid Sequestrants (continued) Demonstrated Therapeutic Benefits Reduce major coronary events Reduce CHD mortality

Drug Therapy Fibric Acids Major actions –Lower LDL-C 5–20% (with normal TG) –May raise LDL-C (with high TG) –Lower TG 20–50% –Raise HDL-C 10–20% Side effects: dyspepsia, gallstones, myopathy Contraindications: Severe renal or hepatic disease

Fibric Acids DrugDose Gemfibrozil600 mg Fenofibrate145/200 mg Bezafibrate400 mg

Simvastatina + Ezetimibe

Age-standardized mortality from cardiovascular disease, i.e. ischaemic heart disease and cerebrovascular disease combined, in European regions (men; age group years; year 2000) J Muller-Nordhorn, et al. Eur Heart J 2008;29:Epub online