Universidade

de São Paulo
Faculdade de Medicina
Instituto do Coração (InCor)

Colesterol um vilåo cujo controle depende de voces

Jose Antonio F. Ramires

Professor Titular de Cardiologia

jramires@incor.usp.br
jramires3@yahoo.com
pubmed : Ramires J A
 2 Sets of
Lipoproteins
0.95 ApoA1 Apo B
Density (g/mL)

1.006

1.02

1.06
1.10
1.20
MAL 5 10 20 240 60 80 1000
Diameter (nm)
 Atherogenic Cholesterol Load
0.95
Density (g/ml)

1.006

1.02

1.06
1.10
1.20
5 10 20 40 60 80 1000
Diameter (nm)
MAL 3
 Non HDL Cholesterol
0.95
Density (g/ml)

1.006

1.02

1.06
1.10
1.20
5 10 20 40 60 80 1000
Diameter (nm)
MAL 4
 Atherogenic Lipoparticles
0.95 Apo B100
Density (g/ml)

1.006

1.02
Apo B48

1.06
1.10
1.20
5 10 20 40 60 80 1000
Diameter (nm)
MAL 5
 Translating Today’s Science into Clinical Practice

On-Treatment LDL-C
is Closely Related to CHD Events in Statin Trials

MAL 6

Erhardt L. Atherosclerosis 2006;185:12-20

MAL 7
 Amer.Men
Hazda
Inuit ATEROSCLEROSE
Ikung
Pygmy
San Mean Total Cholesterol (mg/dL)
50 70 90 110 130 150 170 190 210
(LDL≈50) (LDL≈70)
Pygmy ≈100

Ikung ≈120
Hazda ≈110 American men ≈ 208

Inuit ≈140
San ≈ 120
 METABOLISMO do
COLESTEROL

• Sintese Diaria de um Adulto

800 mg

Local de Sintese
figado – 75 a 95%
Intestino – 5 a 25%
 Redução do risco relativo de morte por DAC/
eventos coronarianos nos Estudos de Prevenção Primária ou
Secundária com vastatinas
AFCAPS/
TexCAPS+ WOSCOPS CARE HPS 4S LIPID TNT
0
REDUÇÃO RELATIVA DO RISCO

–10

–20
(%)

–20%
-24% –24% –22%
–30
–28%

–40 –37%
–42%
–50 PREVENÇÃO PRIMÁRIA PREVENÇÃO SECUNDÁRIA

Estudos independentes, não comparativos, com populações diferentes de pacientes

AFCAP/TEXCAPS=
AFCAP/TEXCAPS= Air Force/texas Coronary Atherosclerosis Prevention Study; WOSCOPS=
WOSCOPS= West of Scotland Coronary Prevention Study; CARE=
CARE= Cholesterol
and Recurrent Events; HPS=
HPS= Heart Protection Study; 4S=
4S= Scandinavian Simvastatin Survival Study; LIPID=
LIPID= Long-term Intervation with Pravastatin in
Ischemic Disease; TNT=
TNT= Treating to New Targets.
Principais eventos coronarianos; morte relacionada à DAC em todos os outros estudos.
+

Downs JR et al JAMA 1998;279(20):1615–1622; Sheperd J et al N Engl J Med 1995;333(20):1301–1307; Sacks FM et al N Engl J Med 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 randomised placebo-controlled trial. Lancet 2002;360: 7-22. 4S study group Lancet 1994;344:1383–1389; LIPID study group N Engl J Med
1998;339(19):1349–1357; LaRosa JC et al. N Engl J Med 2005;352:1-11.
 Metas de LDL-C do ATP III revisadas
e pontos de corte para o tratamento
LDL-C (mg/dL)
NÍVEL P/ NÍVEL P/ CONSIDERAR
CATEGORIA DE RISCO META INICIAR MEV TRATAMENTO FARMACOLÓGICO

Alto risco:
DAC ou equivalente de risco de DAC
<100 ≥ 100
(risco em 10 anos >20%) (opcional: ≥100 (<100: considerar
<70) opções farmacológicas)
Risco moderadamente alto: 2 ou+ <130 ≥130
fatores de risco+ (risco em 10 anos 10– (opcional: ≥130 (100–129: considerar
20%) <100) opções farmacológicas)

Risco moderado:
2 ou + fatores de risco+ (risco em <130 ≥130 ≥160
10 anos <10%)

≥190
Baixo risco:
<160 ≥160 (160–189: medicação p/
0–1 fator de risco+ reduzir LDL-C opcional)

Exceto diabetes mellitus

+

Grundy SM. Circulation 2004;110:227-239.

 Eficácia na redução de LDL-C nas
doses iniciais

Medicação Dose Redução % de LDL- C

Atorvastatina 10 36-38

Ezetimiba/sinvastatina 10/20 50-54

Rosuvastatina 10 46
*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

Goldberg RB, et al. Mayo Clin Proc. 2006;81:1579–1588.

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. Am J Cardiol 2004;93:1487–1494.
Ballantyne CM et al. Am Heart J 2005;149:464–473.
 Doses Mínimas para Atingir ≥50%
de Redução de LDL-C

Medicação Dose (mg/dl) Redução % de LDL- C

Atorvastatina 80 51–54

Ezetimiba/sinvastatina 10/20 50-51

Rosuvastatina 20 52

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. Am J Cardiol 2004;93:1487–1494. Ballantyne CM et al. Am Heart J 2005;149:464–473.
 Ezetimiba/Sinvastatina Reduziu
Significativamente o LDL-C em toda a Faixa Posológica

Doses agrupadas Ezetimiba/Sinvastatina

Rosuvastatina
Eze/Sinva
10/20 a Rosuva Eze/Sinva Rosuva Eze/Sinva Rosuva Eze/Sinva Rosuva
10/80 mg 10 a 40 mg 10/20 mg 10 mg 10/40 mg 20 mg 10/80 mg 40 mg
(n=1.427) (n=1428) (n=476) (n=475) (n=477) (n=478) (n=474) (n=475)
0
Alteração % média na 6a. Semana a

–45
partir do período basal

–45.8%
–50

–51.6% –51.5%*
–55 –52.3%
–54.8%**
–55.8%*
–60 –56.7%

–61%*
–65
*p<0.001
**p<0.01
AA.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
 Mais Pacientes Atingiram a Meta de
LDL <100 mg/dL com Ezetimiba/Sinvastatina

Ezetimiba/Sinvastatina 10/20–10/80 mg (n=1.427)

Rosuvastatina 10–40 mg (n=1.428)

95
% pacientes na meta na 6a.

90
88.2%*
85
81.9%
semana

80
75
70

0
LDL-C alvo <100 mg/dL
*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
 Mais Pacientes Atingiram a Meta de LD
<70 mg/dL com Ezetimiba/Sinvastatina

Ezetimiba/Sinvastatina 10/20–10/80 mg (n=1.427)

Rosuvastatina 10–40 mg (n=1.428)

55
% pacientes na meta na 6a.

50
45
43.5%*
40
semana

35 29.5%
30
25
20

0
LDL-C alvo <70 mg/dL
*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
 Ezetimiba/Sinvastatina Melhorou Outros Parâmetros Lipídicos

Ezetimiba/Sinvastatina 10/20–10/80 mg (n=1.427)

Rosuvastatina 10–40 mg (n=1.428) HDL-C

10 Colesterol 7.6% 7.6%

CT TG Apo B não–HDL
Alteração % média+ na 6a. semana a

0
partir do período basal

–20
–25
–30 –24.6%
–26.2%++
–35
–40
–36.7%
–45 –40%++ –42.3%
–50 –45.3%++ –47.2%
–55 –51.3%++

+
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
 EASE Trial
Reduction in Triglycerides Increase in
•A large proportion of patients in the
p<0.001 High-Density Lipoprotein
trial had diabetes (38.4%) and
(HDL)
p<0.001 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
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 Ezetimibe Placebo

Presented at ACC Scientific Sessions 2004

 EASE Trial
Reduction in LDL Reached Target •In the overall study population, a
p<0.001 LDL Goals larger percent change from baseline
p<0.001
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
mg/dl

LDL goals.

•Results were similar across the

different statin brands and by the
prespecified subgroups of age group,
gender, and diabetes status.

Ezetimibe Placebo Ezetimibe Placebo

Presented at ACC Scientific Sessions 2004

 EASE Trial
Reduction in LDL Reached Target LDL Goals
p<0.001 p<0.001
mg/dl

CHD/CHD Multiple Risk <2 CHD Risk CHD/CHD Multiple Risk <2 CHD Risk
Equivalent Factor Factor Equivalent Factor Factor

•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).

Presented at ACC Scientific Sessions 2004

 EFEITO do EZETIMIBE + SINVASTATINA
sobre o ST em Pacientes com DAC e
Hipercolesterolemia
% de redução do infra SST
100
90
80 *,** =p<0.02
70
60
Basal
50
8 sem.
40 * 16 sem.
30
20 **
10
0
Dieta Sinva+Ezet
20 10
n 39 41
Ramires JAF,... Mansur AP , 2007
 Extenso Programa de Desfechos Clínicos envolvendo mais de 21.000
Pacientes de Alto Risco de Eventos Cardiovasculares

N População de estudo Medicamentos Desfecho primário

~725 HFhe Ezetimiba/ Espessura da

sinvastatina 10/80 mg íntima-média da
Sinvastatina 80 mg carótida

~1873 Estenose aórtica Ezetimiba/ Morte CV, cirurgia

assintomática com LDL-C sinvastatina 10/40 mg aórtica, desfechos
Placebo cardiovasculares
<230 mg/dl

~9000 Doença renal crônica Ezetimiba/ Desfechos CVs (IM,

sinvastatina 10/20 mg AVC,
Placebo revascularização
coronária)
~10,000 Síndrome Coronariana Ezetimiba/ Desfechos CVs
Aguda sinvastatina 10/40 mg (morte, IM, SCA,
Sinvastatina 40 mg 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.
Lipoprotein Metabolism Consists of 2 Interconnected Cascades

ApoB 48

ApoB 100

MAL 26
 Two Types of Lipoproteins are Atherogenic in
Humans
Apo B100 containing Apo B48 containing
LDL Chylomicron Remnants
B100 B48
TG
TG
CE
Hepatic Intestinal
CE TG

Apolipoprotein B fragments

Cholesteryl ester
MAL 27
Model for the Major Steps in Reverse Cholesterol Transport

Catabolism

Lipid
Removal
Apo A1
Apo A1

Processing
LCAT
Maturatio
n

Peripheral Tissue
MAL 28
Oram J. Trends in Molecular Medicine 2002;8:168-173
 HDL Metabolism
and Reverse Cholesterol
Transport

MAL 29
Rader D. Curr Athero Reports 2004;6:398-405
 Cholesterol and Isoprenoid Biosynthesis Network

MAL 30
Schmitz G. Vascular Pharmacology 2006;44:75-89
 Major Pathways in the Absorption and Intracellular Traffic
of Cholesterol and Plant Sterols in the Mucosa Cell

MAL 31
on Bergmann K. Am J Cardiol 2005;96(suppl): 10D-14D
 Intestinal Cholesterol Absorption is a Multistep Process
that is Regulated by Multiple Genes

Lumen Enterocyte Lymph

Sterol Influx Transporter

MAL 32
Lammert F. Gastroenterology 2005;129:718-734
MAL 33
 Universidade
de São Paulo
Faculdade de Medicina
Instituto do Coração (InCor)

Aos amigos da MSD :

Obrigado
pela

ATENÇÅO