Adult Treatment Panel III (ATP III) Guidelines

May 2001

Ipercolesterolemie famigliari

Ipercolesterolemie e rischio cardio vascolare globale

Chilomicroni (apo B-48, C, E)

MACROFAGO

VLDLApo B-100Apo C, E

IDL

LDLApo B-100

HDL3Apo AI-II

HDL2

TG Fatty AcidsCOL

trasportoinverso

Site of Synthesis of Lipoproteins

CM VLDL IDL LDL HDL

Lipoprotein Nomenclatureand Composition

Major apoB apoB apoB apoB apoA-IProtein

Major TG TG CE CE CELipid

CM= chylomicron TG=triglycerideVLDL= very low density lipoprotein CE= cholesteryl esterIDL= intermediate density lipoproteinLDL= low density lipoproteinHDL= high density lipoproteinApo = apolipoprotein

Iperlipoproteinemie secondo FredriksonClassificazione fenotipica

V Chilomicroni, VLDL TG & ColIV VLDL TG & Col

III IDL, VLDL, Chilomicroni Col & TG (1/1)IIb LDL & VLDL Col & TGIIa LDL Col

I Chilomicroni TG

Iperlipoproteinemie genetiche

Ipercol Fam IV o V 2-3/1000 AD ?

Iperlipidemia IIb o IV 3-5/1000 AD ?FamiliareCombinata

FH IIa o IIb 1/500 AD def recettore LDLFDA IIa 1/500 AD Apo B100 defPoligenica IIa ? ? ?Disß III ? AR Apo E2E2

Iperchilo I o V rara + AR Deficit LPL/Apo C-II

Iper Col > Iper TG

Iper TG > Iper Col

Diagnosiiperlipoproteinemie 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

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 & HomFDA apo B-100

PH

T2DM/T1DMIpotiroidismoCushingIRCSindrome NefrosicaColestasiObesità

Iperlipemia iatrogena

AlcoholHigh-CARBO DietEstrogeniTiclopidinaDiureticiß-blockGlucocorticoidi

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

rischiorelativo

1

2

3

0no DMno IMA

no DMIMA

DMno IMA

DMIMA

Mukamal KJ et al Diabetes Care 24; 1422, 2001

rischio relativo di mortalità CVD

NEFA

Il paradigma dell’aumentato flusso dei NEFA

Perseghin G. et al. Curr Opin Lipidol, 2005

DietaSedentarietà

Geni

Eccesso di grasso viscerale e dislipidemia

Pouliot MC et al. Diabetes 1992;41:826-34

310

248

186

124

62

0

60

45

30m

g/d

L

mg

/dL

Trigliceridi

Magri

Colesterolo HDL

Grasso viscerale(soggetti obesi)

Basso Alto Magri

Grasso viscerale(soggetti obesi)

Basso Alto

L’eccesso di grasso viscerale promuoveun fenotipo aterogeno Elevati trigliceridi, basso C-HDL e

elevate particelle piccole e dense di C-LDL

C-LDL normale C-LDL normaleLDL dense

TGC-HDL

TGC-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 CVDPRIORITA’

pazienti con eventivascolari

(%)

0

20

10

Placebo SIMVA

HPS Lancet 360; 7, 2002

Terapia farmacologicaEFFICACIA delle STATINE

Modulazione dell’intervento

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%: 130

10-year risk <10%: 160

130<1302+ 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 farmacologicaEFFICACIA delle STATINE

Colesterolo totale 20-40%

LDL-C 30-50%

Trigliceridi 5-20%

HDL-C 5%

Terapia farmacologicaEFFETTI PLEIOTROPICI delle STATINE

• Infiammazione•Funzione endoteliale

• Stabilità di placca

Drug TherapyHMG 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 alAm J Cardiol 81: 582, 1998

rosuva

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

Drugs Features

Drug TherapyBile 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

Cholestyramine 4–16 g

Bile Acid Sequestrants (continued)

Demonstrated Therapeutic Benefits

• Reduce major coronary events

• Reduce CHD mortality

Drug TherapyFibric 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

Drug Dose

• Gemfibrozil 600 mg

• Fenofibrate 145/200 mg

• Bezafibrate 400 mg

Simvastatina+

Ezetimibe

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