Universidadede São PauloFaculdade de Medicina
Instituto do Coração (InCor)
Colesterol um vilåo cujo controle depende de voces
Jose Antonio F. RamiresProfessor Titular de Cardiologia
[email protected]@yahoo.compubmed : Ramires J A
MAL 2
2 Sets of 2 Sets of LipoproteinsLipoproteins
0.950.95
1.0061.006
1.021.02
1.061.06
1.101.10
1.201.20
Den
sity
(g/
mL
)D
ensi
ty (
g/m
L)
55 1010 2020 4040 6060 8080 10001000Diameter (nm)Diameter (nm)
ApoA1ApoA1 Apo BApo B
MAL 3
Atherogenic Cholesterol LoadAtherogenic Cholesterol Load
0.950.95
1.0061.006
1.021.02
1.061.061.101.10
1.201.20
55 1010 2020 4040 6060 8080 10001000
Den
sity
(g/
ml)
Den
sity
(g/
ml)
Diameter (nm)Diameter (nm)
MAL 4
Non HDL CholesterolNon HDL Cholesterol
0.950.95
1.0061.006
1.021.02
1.061.061.101.10
1.201.20
55 1010 2020 4040 6060 8080 10001000
Den
sity
(g/
ml)
Den
sity
(g/
ml)
Diameter (nm)Diameter (nm)
MAL 5
Atherogenic LipoparticlesAtherogenic Lipoparticles
0.950.95
1.0061.006
1.021.02
1.061.061.101.10
1.201.20
55 1010 2020 4040 6060 8080 10001000
Den
sity
(g/
ml)
Den
sity
(g/
ml)
Diameter (nm)Diameter (nm)
Apo B100
Apo B48
MAL 6
On-Treatment LDL-C is Closely Related to CHD Events in Statin Trials
Erhardt L. Atherosclerosis 2006;185:12-20
Translating Today’s Science into Clinical Practice
MAL 7
(LDL≈50) (LDL≈70)
Mean Total Cholesterol (mg/dL)Mean Total Cholesterol (mg/dL)
50 70 90 110 130 150 170 190 210
Ikung ≈120Ikung ≈120
Ikung
Hazda ≈110Hazda ≈110
Hazda
Amer.Men
American men ≈ 208American men ≈ 208
Pygmy
Pygmy ≈100Pygmy ≈100
Inuit ≈140Inuit ≈140
Inuit
San ≈ 120San ≈ 120
San
ATEROSCLEROSE
METABOLISMO do METABOLISMO do COLESTEROLCOLESTEROL
• Sintese Diaria de um AdultoSintese Diaria de um Adulto800 mg
Local de Sintesefigado – 75 a 95%
Intestino – 5 a 25%
Redução do risco relativo de morte por DAC/Redução do risco relativo de morte por DAC/eventos coronarianos nos Estudos de Prevenção Primária ou eventos coronarianos nos Estudos de Prevenção Primária ou
Secundária com vastatinasSecundária com vastatinas
RED
UÇ
ÃO
RELA
TIV
A D
O R
ISC
OR
ED
UÇ
ÃO
RELA
TIV
A D
O R
ISC
O(%
)(%
)
AFCAPS/AFCAPS/TexCAPSTexCAPS++ 4S4S
Estudos independentes, não comparativos, com populações diferentes de pacientesEstudos independentes, não comparativos, com populações diferentes de pacientes
AFCAP/TEXCAPSAFCAP/TEXCAPS= Air Force/texas Coronary Atherosclerosis Prevention Study; = Air Force/texas Coronary Atherosclerosis Prevention Study; WOSCOPSWOSCOPS= West of Scotland Coronary Prevention Study; = West of Scotland Coronary Prevention Study; CARECARE= Cholesterol = Cholesterol and Recurrent Events; and Recurrent Events; HPSHPS= Heart Protection Study; = Heart Protection Study; 4S4S= Scandinavian Simvastatin Survival Study; = Scandinavian Simvastatin Survival Study; LIPIDLIPID= Long-term Intervation with Pravastatin in = Long-term Intervation with Pravastatin in Ischemic Disease; Ischemic Disease; TNTTNT= Treating to New Targets.= Treating to New Targets.++Principais eventos coronarianos; morte relacionada à DAC em todos os outros estudos.Principais eventos coronarianos; morte relacionada à DAC em todos os outros estudos.
Downs JR et al Downs JR et al JAMAJAMA 1998;279(20):1615–1622; Sheperd J et al 1998;279(20):1615–1622; Sheperd J et al N Engl J MedN Engl J Med 1995;333(20):1301–1307; Sacks FM et al 1995;333(20):1301–1307; Sacks FM et al N Engl J MedN Engl J Med 1996;335:1001–1009; 1996;335:1001–1009; Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: A Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: A randomised placebo-controlled trial. randomised placebo-controlled trial. LancetLancet 2002;360: 7-22. 4S study group 2002;360: 7-22. 4S study group LancetLancet 1994;344:1383–1389; LIPID study group 1994;344:1383–1389; LIPID study group N Engl J MedN Engl J Med 1998;339(19):1349–1357; LaRosa JC et al. 1998;339(19):1349–1357; LaRosa JC et al. N Engl J MedN Engl J Med 2005;352:1-11. 2005;352:1-11.
WOSCOPSWOSCOPS CARECARE LIPIDLIPID00
––1010
––2020
––3030
––4040
––5050
––37%37%
––28%28%
––20%20%
––42%42%
––24%24%
PREVENÇÃO PRIMÁRIAPREVENÇÃO PRIMÁRIA PREVENÇÃO SECUNDÁRIAPREVENÇÃO SECUNDÁRIA
––22%22%
TNTTNTHPSHPS
-24%-24%
Risco moderadamente alto: 2 ou+ fatores de risco+ (risco em 10 anos 10–20%)
130 (100–129: considerar
opções farmacológicas)130
<130(opcional:
<100)
190(160–189: medicação p/ reduzir LDL-C opcional)
160<160Baixo risco: 0–1 fator de risco+
160130<130Risco moderado:2 ou + fatores de risco+ (risco em 10 anos <10%)
100100(<100(<100: considerar : considerar
opções farmacológicasopções farmacológicas))100
<100<100((opcional: opcional:
<70)<70)
Alto risco: DAC ou equivalente de risco de DAC (risco em 10 anos >20%)
NÍVEL P/ CONSIDERAR NÍVEL P/ CONSIDERAR
TRATAMENTO FARMACOLÓGICOTRATAMENTO FARMACOLÓGICO
NÍVEL P/NÍVEL P/INICIAR MEVINICIAR MEV
METAMETA
LDL-C (mg/dL)LDL-C (mg/dL)
Metas de LDL-C do ATP III revisadasMetas de LDL-C do ATP III revisadase pontos de corte para o tratamentoe pontos de corte para o tratamento
CATEGORIA DE RISCOCATEGORIA DE RISCO
++Exceto diabetes mellitusExceto diabetes mellitus
Grundy SM. Grundy SM. CirculationCirculation 2004;110:227-239 2004;110:227-239..
Eficácia na redução de LDL-C nas Eficácia na redução de LDL-C nas doses iniciaisdoses iniciais
M.H. Davidson et al. Lipid-Altering Efficacy and Safety of Ezetimibe/Simvastatin Versus Rosuvastatin Patients with Primary Hypercholesterolemia - Pôster apresentado no ISA (International Society of Atherosclerosis) em 18 de Junho de 2006, Roma, Itália. Ballantyne CM et al. Ballantyne CM et al. Am J CardiolAm J Cardiol 2004;93:1487–1494. 2004;93:1487–1494. Ballantyne CM et al. Ballantyne CM et al. Am Heart JAm Heart J 2005;149:464–473. 2005;149:464–473.
4610Rosuvastatina
50-5410/20Ezetimiba/sinvastatina
Redução % de LDL- CDoseMedicação
36-3810Atorvastatina
Goldberg RB, et al. Mayo Clin Proc. 2006;81:1579–1588.
*p<0.001 vs. rosuvastatina
A.L.Catapano, M.H. Davidson et al. Lipid-Altering Efficacy of the Ezetimibe/Simvastatin single tablet Versus Rosuvastatin in Hypercholesterolemic Patients – Curr Med Res Opin, 22 (10), 2006: 2041-2053
Doses Mínimas para Atingir Doses Mínimas para Atingir 50% 50% de Redução de LDL-Cde Redução de LDL-C
M.H. Davidson et al. Lipid-Altering Efficacy and Safety of Ezetimibe/Simvastatin Versus Rosuvastatin Patients with Primary Hypercholesterolemia - Pôster apresentado no ISA (International Society of Atherosclerosis) em 18 de Junho de 2006, Roma, Itália. Ballantyne CM et al. Ballantyne CM et al. Am J CardiolAm J Cardiol 2004;93:1487–1494. Ballantyne CM et al. 2004;93:1487–1494. Ballantyne CM et al. Am Heart JAm Heart J 2005;149:464–473. 2005;149:464–473.
5220Rosuvastatina
50-5110/20Ezetimiba/sinvastatina
Redução % de LDL- CDose (mg/dl)Medicação
51–5480Atorvastatina
Ezetimiba/Sinvastatina Reduziu Ezetimiba/Sinvastatina Reduziu
Significativamente o LDL-C em toda a Faixa PosológicaSignificativamente o LDL-C em toda a Faixa Posológica
0
–50
–55
–45
–65
–60
–51.5%*
–45.8%
–54.8%**–52.3%
–61%*
–56.7%
*p<0.001 **p<0.01AA.L.Catapano, M.H. Davidson et al. Lipid-Altering Efficacy of the Ezetimibe/Simvastatin single tablet Versus Rosuvastatin in Hypercholesterolemic Patients – Curr Med Res Opin, 22 (10), 2006: 2041-2053
Eze/Sinva10/40 mg
(n=477)
Rosuva20 mg(n=478)
Eze/Sinva 10/20 mg
(n=476)
Rosuva10 mg(n=475)
Eze/Sinva 10/80 mg
(n=474)
Rosuva40 mg(n=475)
–55.8%*
–51.6%
Eze/Sinva 10/20 a
10/80 mg(n=1.427)
Rosuva 10 a 40 mg
(n=1428)
Alt
eraç
ão %
méd
ia n
a 6a
. Sem
ana
a
par
tir
do
per
íod
o b
asal
Ezetimiba/SinvastatinaRosuvastatina
Doses agrupadas
81.9%
88.2%*
Mais Pacientes Atingiram a Meta de Mais Pacientes Atingiram a Meta de LDL <100 mg/dL com Ezetimiba/SinvastatinaLDL <100 mg/dL com Ezetimiba/Sinvastatina
*p<0.001 vs. rosuvastatina A.L.Catapano, M.H. Davidson et al. Lipid-Altering Efficacy of the Ezetimibe/Simvastatin single tablet Versus Rosuvastatin in Hypercholesterolemic Patients – Curr Med Res Opin, 22 (10), 2006: 2041-2053
% p
acie
ntes
na
met
a na
6a.
se
man
a
95
85
80
75
70
LDL-C alvo <100 mg/dL0
Ezetimiba/Sinvastatina 10/20–10/80 mg (n=1.427)Rosuvastatina 10–40 mg (n=1.428)
90
29.5%
43.5%*
Mais Pacientes Atingiram a Meta de LDL Mais Pacientes Atingiram a Meta de LDL <70 mg/dL com Ezetimiba/Sinvastatina<70 mg/dL com Ezetimiba/Sinvastatina
*p<0.001 vs. rosuvastatina A.L.Catapano, M.H. Davidson et al. Lipid-Altering Efficacy of the Ezetimibe/Simvastatin single tablet Versus Rosuvastatin in Hypercholesterolemic Patients – Curr Med Res Opin, 22 (10), 2006: 2041-2053
% p
acie
ntes
na
met
a na
6a.
se
man
a
55
45
35
30
20
LDL-C alvo <70 mg/dL0
Ezetimiba/Sinvastatina 10/20–10/80 mg (n=1.427)Rosuvastatina 10–40 mg (n=1.428)
40
25
50
Ezetimiba/Sinvastatina Melhorou Outros Parâmetros LipídicosEzetimiba/Sinvastatina Melhorou Outros Parâmetros LipídicosA
lter
ação
% m
édia
+ n
a 6a
. sem
ana
a
par
tir
do
per
íod
o b
asal
10
–30
–20
HDL-C
CT
–40%++
–40
Ezetimiba/Sinvastatina 10/20–10/80 mg (n=1.427)Rosuvastatina 10–40 mg (n=1.428)
0TG
–50
–36.7%
–26.2%++–24.6%
7.6% 7.6%
–25
–35
–45
–45.3%++
–42.3%
–51.3%++
–47.2%
–55
Apo BColesterol não–HDL
+Exceto para os TGs (alterações porcentuais medianas); ++p<0.001 vs. rosuvastatina A.L.Catapano, M.H. Davidson et al. Lipid-Altering Efficacy of the Ezetimibe/Simvastatin single tablet Versus Rosuvastatin in Hypercholesterolemic Patients – Curr Med Res Opin, 22 (10), 2006: 2041-2053
Reduction in Triglyceridesp<0.001
Presented at ACC Scientific Sessions 2004Presented at ACC Scientific Sessions 2004
EASE TrialEASE Trial•A large proportion of patients in the trial had diabetes (38.4%) and metabolic syndrome by NCEP ATP III criteria (60%).
•Baseline LDL levels were 129 mg/dl in the overall population, 123 mg/dl in the coronary heart disease (CHD) or CHD risk equivalent group, 147 mg/dl in the multiple risk factors group, and 167 mg/dl in the <2 risk factors group.
•The ezetimibe arm had a larger reduction in triglycerides and a larger increase in high-density lipoprotein (HDL) levels.
Ezetimibe Placebo
mg/
dl
Increase inHigh-Density Lipoprotein
(HDL)p<0.001
Ezetimibe Placebo
Reduction in LDLp<0.001
Presented at ACC Scientific Sessions 2004Presented at ACC Scientific Sessions 2004
EASE TrialEASE Trial•In the overall study population, a larger percent change from baseline in LDL levels occurred in the ezetimibe arm versus placebo.
•The follow-up LDL level in the ezetimibe arm was 95 mg/dl.
•A larger percentage of patients in the ezetimibe arm reached target LDL goals.
•Results were similar across the different statin brands and by the prespecified subgroups of age group, gender, and diabetes status.
Ezetimibe Placebo
Reached Target LDL Goals
p<0.001
mg/
dl
Ezetimibe Placebo
Reduction in LDLp<0.001
Presented at ACC Scientific Sessions 2004Presented at ACC Scientific Sessions 2004
EASE TrialEASE TrialReached Target LDL Goals
p<0.001
mg/
dl
•Similar results were observed in the CHD/CHD risk equivalent subgroup, the multiple risk factor subgroup, and the <2 CHD risk factor subgroup.
•There were no increases in the frequency of alanine aminotransferase (ALT) ≥3 times upper limit of normal (ULN) (0.4% for ezetimibe vs. 0.2% for placebo), aspartate aminotransferase (AST) ≥3 times ULN (0.2% vs. 0.1%), or creatine kinase (CK) ≥10 times ULN (0 in both groups).
CHD/CHD Equivalent
Multiple Risk Factor
<2 CHD Risk Factor
CHD/CHD Equivalent
Multiple Risk Factor
<2 CHD Risk Factor
EFEITO do EZETIMIBE + SINVASTATINA EFEITO do EZETIMIBE + SINVASTATINA sobre o ST em Pacientes com DAC e sobre o ST em Pacientes com DAC e
HipercolesterolemiaHipercolesterolemia
0
10
20
30
40
50
60
70
80
90
100
Dieta Sinva+Ezet
Basal
8 sem.
16 sem.
% de redução do infra SST
*
**
*,** =p<0.02
20 10
n 39 41 Ramires JAF,... Mansur AP , 2007
Extenso Programa de Desfechos Clínicos envolvendo mais de 21.000 Pacientes Extenso Programa de Desfechos Clínicos envolvendo mais de 21.000 Pacientes de Alto Risco de Eventos Cardiovascularesde Alto Risco de Eventos Cardiovasculares
N População de estudo Medicamentos Desfecho primário
~725 HFhe Ezetimiba/sinvastatina 10/80 mgSinvastatina 80 mg
Espessura da íntima-média da carótida
~1873 Estenose aórtica assintomática com LDL-C
<230 mg/dl
Ezetimiba/sinvastatina 10/40 mgPlacebo
Morte CV, cirurgia aórtica, desfechos cardiovasculares
~9000 Doença renal crônica Ezetimiba/sinvastatina 10/20 mgPlacebo
Desfechos CVs (IM, AVC, revascularização coronária)
~10,000 Síndrome Coronariana Aguda
Ezetimiba/sinvastatina 10/40 mgSinvastatina 40 mg
Desfechos CVs (morte, IM, SCA, revascularização)
Adaptado de Kastelein JJP, et al. Am Heart J. 2005;149:234–239; Baigent C, Landry M. Kidney Int. 2003;63(suppl 84):S207–S210; Oxford Clinical Trial Service Unit. The Study of Heart and Renal Protection (SHARP). Disponível em: http://www.ctsu.ox.ac.uk/ ~sharp/. Acessado em juho de 2005; Rossebo A, et al, for the SEAS Steering Committee. Apresentado no XIII International Symposium on Atherosclerosis em 23 de setembro a 2 de outubro de 2003, em Kyoto, Japão. Poster 3P-0870; Schering-Plough. IMPROVE-IT: Examining outcomes in subjects with acute coronary syndrome: Vytorin (ezetimiba/sinvastatina) vs sinvastatina (Estudo P04103). Disponível em: http://www.clinicaltrials.gov/ct/show/NCT00202878. Acessado em novembro de 2006.
MAL 26
Kwiterovich P. Am J Cardiol 2000;86:5-10
Lipoprotein Metabolism Consists of 2 Interconnected Cascades
ApoB 48
ApoB 100
MAL 27
Two Types of Lipoproteins are Atherogenic in Two Types of Lipoproteins are Atherogenic in HumansHumans
B48B100
CE TG
TGCE
Apo B100 containing LDL
Apo B100 containing LDL
Apo B48 containing Chylomicron Remnants
Apo B48 containing Chylomicron Remnants
Apolipoprotein B fragmentsApolipoprotein B fragments
Cholesteryl esterCholesteryl ester
TG
Hepatic Intestinal
MAL 28
Oram J. Trends in Molecular Medicine 2002;8:168-173
Catabolism
Apo A1Apo A1
Lipid Removal
Peripheral Tissue
Processing LCATMaturatio
n
Model for the Major Steps in Reverse Cholesterol Transport
MAL 29
HDL Metabolism HDL Metabolism
and Reverse Cholesterol and Reverse Cholesterol
TransportTransport
Rader D. Curr Athero Reports 2004;6:398-405
MAL 30
Cholesterol and Isoprenoid Biosynthesis Network
Schmitz G. Vascular Pharmacology 2006;44:75-89
MAL 31
Major Pathways in the Absorption and Intracellular Traffic of Cholesterol and Plant Sterols in the Mucosa Cell
Von Bergmann K. Am J Cardiol 2005;96(suppl): 10D-14D
MAL 32
Intestinal Cholesterol Absorption is a Multistep Process that is Regulated by Multiple Genes
Sterol Influx Transporter
Lammert F. Gastroenterology 2005;129:718-734
Lumen Enterocyte Lymph
MAL 33
Universidadede São PauloFaculdade de Medicina
Instituto do Coração (InCor)
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