Adult Treatment Panel III (ATP III) Guidelines May 2001

1. Adult Treatment Panel III (ATP III) GuidelinesMay 2001 Ipercolesterolemie famigliari Ipercolesterolemie e rischio cardio vascolare globale

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

3. Lipoprotein Nomenclature and Composition CM VLDL IDL LDL HDL MajorapoB apoB apoB apoB apoA-I Protein MajorTG TG CE CE CE Lipid CM= chylomicron TG=triglyceride VLDL= very low density lipoprotein CE= cholesteryl ester IDL= intermediate density lipoprotein LDL= low density lipoprotein HDL= high density lipoprotein Apo = apolipoprotein

4. Iperlipoproteinemie secondo Fredrikson Classificazione fenotipica I Chilomicroni TG IIa LDL Col IIb LDL & VLDL Col & TG III IDL, VLDL, Chilomicroni Col & TG (1/1) IV VLDL TG & Col V Chilomicroni, VLDL TG & Col

5. Iperlipoproteinemie genetiche Iper Col > Iper TG FH IIa o IIb 1/500 AD def recettore LDL FDA IIa 1/500 AD Apo B100 def Poligenica IIa ? ? ? Disß III ? AR Apo E2E2 Iper TG > Iper Col Iperchilo I o V rara + AR Deficit LPL/Apo C-II Ipercol Fam IV o V 2-3/1000 AD ? Iperlipidemia IIb o IV 3-5/1000 AD ? Familiare Combinata

6. 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 190 - 220 mg/dl ?? Apo B cut off

7. Adult Treatment Panel III (ATP III) GuidelinesMay 2001 National Cholesterol Education Program

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

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

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

11. Diabete e CVD rischio relativo di mortalità CVD 3 2 rischio relativo 1 0 DM no IMA no DM no IMA DM IMA no DM IMA Mukamal KJ et al Diabetes Care 24; 1422, 2001

12. Il paradigma dell’aumentato flusso dei NEFA Geni Dieta Sedentarietà NEFA Perseghin G. et al. Curr Opin Lipidol, 2005

13. Trigliceridi Colesterolo HDL 310 60 248 186 mg/dL mg/dL 45 124 62 30 0 Basso Alto Magri Basso Alto Magri Grasso viscerale (soggetti obesi) Grasso viscerale (soggetti obesi) Eccesso di grasso viscerale e dislipidemia Pouliot MC et al. Diabetes 1992;41:826-34

14.  grasso viscerale Magri TG C-HDL TG C-HDL C-LDLnormale LDL dense C-LDL normale Rischio CHD L’eccesso di grasso viscerale promuoveun fenotipo aterogeno Elevati trigliceridi, basso C-HDL eelevate particelle piccole e dense di C-LDL Despres JP. Ann Med 2001;33:534-41

15. Fattori di Rischio Cardiovascolare

16. Rischio Cardiovascolare Globale

17. Diabete e CVD PRIORITA’ UKPDS BMJ316; 823, 1998

18. Terapia farmacologica EFFICACIA delle STATINE 20 pazienti con eventi vascolari (%) 10 0 Placebo SIMVA HPS Lancet 360; 7, 2002

24. Modulazione dell’intervento

25. Risk Category LDL Goal(mg/dL) LDL Level at Which to Initiate Therapeutic Lifestyle Changes (TLC) (mg/dL) LDL Level at Which to ConsiderDrug Therapy (mg/dL) CHD or CHD Risk Equivalents(10-year risk >20%) <100 100 130 (100–129: drug optional) 2+ Risk Factors (10-year risk 20%) <130 130 10-year risk 10–20%: 130 10-year risk <10%: 160 0–1 Risk Factor <160 160 190 (160–189: LDL-lowering drug optional) LDL Cholesterol Goals and Cutpoints for Therapeutic Lifestyle Changes (TLC)and Drug Therapy in Different Risk Categories

26. Colesterolo totale 20-40% LDL-C 30-50% Trigliceridi 5-20% HDL-C 5% Terapia farmacologica EFFICACIA delle STATINE Terapia farmacologica EFFETTI PLEIOTROPICI delle STATINE • Infiammazione • Funzione endoteliale • Stabilità di placca

27. 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)

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

29. Drugs Features Prava Simva Fluva Atorva/Rosuva Emivita CYP 450 Int Warfarin Int Digitale Lipofilia 2h 3h 3h 15h no yes yes yes yes yes no yes no yes yes yes no yes no yes

30. 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)

31. Bile Acid Sequestrants DrugDose Cholestyramine 4–16 g

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

33. 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

34. Fibric Acids DrugDose • Gemfibrozil 600 mg • Fenofibrate 145/200 mg • Bezafibrate 400 mg

35. Simvastatina+Ezetimibe

38. Age-standardized mortality from cardiovascular disease, i.e. ischaemic heart disease and cerebrovascular disease combined, in European regions (men; age group 45-74 years; year 2000) J Muller-Nordhorn, et al. Eur Heart J 2008;29:Epub online