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Ipercolesterolemie
famigliari
Ipercolesterolemie e
rischio cardio vascolare
globale
Adult Treatment Panel III
(ATP III) Guidelines
May 2001
Site of
Synthesis of
Lipoproteins
VLDL
Chilomicroni (apo B-48, C, E)
Apo B-100
Apo C, E
HDL2
trasporto
inverso
HDL3
Apo AI-II
MACROFAGO
IDL
LDL
Apo B-100
COL
TG Fatty
Acids
Lipoprotein Nomenclature
and Composition
CM
VLDL
IDL
LDL
Major
Protein
apoB
apoB
apoB
apoB
apoA-I
Major
Lipid
TG
TG
CE
CE
CE
CM= chylomicron
VLDL= very low density lipoprotein
IDL= intermediate density lipoprotein
LDL= low density lipoprotein
HDL= high density lipoprotein
Apo = apolipoprotein
HDL
TG=triglyceride
CE= cholesteryl ester
Iperlipoproteinemie secondo Fredrikson
Classificazione fenotipica
I
Chilomicroni
TG
IIa
IIb
III
IV
V
LDL
LDL & VLDL
IDL, VLDL, Chilomicroni
VLDL
Chilomicroni, VLDL
Col
Col & TG
Col & TG (1/1)
TG & Col
TG & Col
Iperlipoproteinemie genetiche
Iper Col > Iper TG
FH
FDA
Poligenica
Disß
IIa o IIb
IIa
IIa
III
1/500
1/500
?
?
AD
AD
?
AR
def recettore LDL
Apo B100 def
?
Apo E2E2
Iper TG > Iper Col
Iperchilo
IoV
rara +
AR
Deficit LPL/Apo C-II
Ipercol Fam
IV o V
2-3/1000
AD
?
3-5/1000
AD
?
Iperlipidemia IIb o IV
Familiare
Combinata
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
Apo B cut off
?? LDL 190 - 220 mg/dl ??
National Cholesterol Education
Program
Adult Treatment Panel III
(ATP III) Guidelines
May 2001
ATP I & ATP II
MAJOR GOAL OF THERAPY
LDL-CHOLESTEROL
MAJOR TARGETS OF THERAPY
FH Het & Hom
FDA apo B-100
PH
Iperlipoproteinemie secondarie
T2DM/T1DM
Ipotiroidismo
Cushing
IRC
Sindrome Nefrosica
Colestasi
Obesità
Iperlipemia iatrogena
Alcohol
High-CARBO Diet
Estrogeni
Ticlopidina
Diuretici
ß-block
Glucocorticoidi
New Features of ATP III
Focus on Multiple Risk Factors
Framingham projections of 10-year CHD risk
Diabetes: CHD risk equivalent
Multiple metabolic risk factors
(metabolic syndrome)
Diabete e CVD
rischio relativo di mortalità CVD
3
rischio
relativo
2
1
0
no DM
no IMA
no DM
IMA
DM
no IMA
DM
IMA
Mukamal KJ et al Diabetes Care 24; 1422, 2001
Il paradigma dell’aumentato
flusso dei NEFA
Geni
Dieta
Sedentarietà
NEFA
Perseghin G. et al. Curr Opin Lipidol, 2005
Eccesso di grasso viscerale e
dislipidemia
Trigliceridi
Colesterolo HDL
310
60
186
mg/dL
mg/dL
248
124
45
62
0
30
Magri
Basso
Alto
Grasso viscerale
(soggetti obesi)
Magri
Basso
Alto
Grasso viscerale
(soggetti obesi)
Pouliot MC et al. Diabetes 1992;41:826-34
L’eccesso di grasso viscerale promuove
un fenotipo aterogeno
Elevati trigliceridi, basso C-HDL e
elevate particelle piccole e dense di C-LDL
Magri
 grasso
viscerale
TG
C-HDL
TG
C-HDL
C-LDL normale
C-LDL normale
LDL dense
Rischio CHD
Despres JP. Ann Med 2001;33:534-41
Fattori di Rischio Cardiovascolare
Rischio Cardiovascolare Globale
Diabete e CVD
PRIORITA’
UKPDS BMJ 316; 823, 1998
Terapia farmacologica
EFFICACIA delle STATINE
20
pazienti con eventi
vascolari
10
(%)
0
Placebo
SIMVA
HPS Lancet 360; 7, 2002
Modulazione dell’intervento
LDL Cholesterol Goals and Cutpoints for Therapeutic
Lifestyle Changes (TLC)
and Drug Therapy in Different Risk Categories
Risk Category
CHD or CHD Risk
Equivalents
(10-year risk >20%)
LDL Goal
(mg/dL)
<100
LDL Level at Which
to Initiate
Therapeutic
Lifestyle Changes
(TLC) (mg/dL)
LDL Level at Which
to Consider
Drug Therapy
(mg/dL)
100
130
(100–129: drug
optional)
10-year risk 10–20%:
130
2+ Risk Factors
(10-year risk 20%)
<130
130
10-year risk <10%:
160
0–1 Risk Factor
<160
160
190
(160–189: LDLlowering drug
optional)
Terapia farmacologica
EFFICACIA delle STATINE
Colesterolo totale
20-40%
LDL-C
30-50%
Trigliceridi
5-20%
HDL-C
5%
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?
prava
The Curves Study
fluva
lova
simva
rosuva
atorva
Jones P et al
Am J Cardiol 81: 582, 1998
Drugs Features
Prava
Simva
Fluva
Atorva/Rosuva
Emivita
2h
3h
3h
15h
CYP 450
no
yes
yes
yes
Int Warfarin
yes
yes
no
yes
Int Digitale
no
yes
yes
yes
Lipofilia
no
yes
no
yes
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
Drug
Dose
Cholestyramine
4–16 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
Drug
• Gemfibrozil
• Fenofibrate
• Bezafibrate
Dose
600 mg
145/200 mg
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