Diabetes mellitus e doença cardiovascular Bernardo Wajchenberg; Antonio Lerário, Roberto Tadeu

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e Doença Cardiovascular 
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Bernardo Léo Wajchenberg 
Antonio Carlos Lerário 
Roberto Tadeu B. Betti 
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e Doença Cardiovascular 
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Diabetes Mellitus e Doença Cardiovascular 
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W159d 
Wajchenberg, Bernardo Leo 
Diabetes mellitus e doença cardiovascular/ Bernardo Léo Wajchenberg, Antonio 
Carlos Lerário, Roberto Tadeu B. Betti. - São Paulo: A. C. Farmacêutica, 2011. 
112 p. ; 21 cm 
Inclui bibliografia 
1. Coração - Doenças - Fatores de risco. 2. Sistema cardiovascular - Doenças -
Fatores de risco. 2. Diabetes - Complicações e sequelas. 3. Diabéticos. 1. Lerá rio, 
Antônio Carlos. li. Betti, Roberto. Ili. Título. 
11-5444. 
029146 
CDD: 616.12 
CDU: 616.12 
Bernardo Léo Wajchenberg 
CRM: 2471-SP 
""""uto res 
Professor Emérito da Faculdade de Medicina da Universidade de São Paulo - USP. 
Professor Titular de Endocrinologia pela Faculdade de Medicina da Universidade de São 
Paulo. Médico Coordenador do Núcleo de Diabetes e Coração do lnCor - Instituto do 
Coração do Hospital das Clínicas da Universidade de São Paulo 
Antonio Carlos Lerário 
CRM: 13821-SP 
Professor Livre Docente do Departamento de Clínica Médica da Faculdade de Medicina da 
Universidade de São Paulo - USP. Doutor em Endocrinologia pela Faculdade de Medicina 
da USP. Médico Assistente do Núcleo de Diabetes e Coração do lnCor - Instituto do 
Coração do Hospital das Clínicas da Universidade de São Paulo. Diretor da Sociedade 
Brasileira de Diabetes 
Roberto Tadeu B. Betti 
CRM: 29857-SP 
Doutor em Ciências pela Universidade de São Paulo - USP. Médico Assistente do 
Núcleo de Diabetes e Coração do lnCor - Instituto do Coração do Hospital das Clínicas 
da Universidade de São Paulo. Médico Coordenador do Centro de Diabetes e Doenças 
Metabólicas do Hospital Alemão Oswaldo Cruz 
/ . 
....,umar10 
1 Epidemiologia da moléstia macrovascular no diabetes tipo 2, 1 
2 Síndrome metabólica e doença macrovascular, 7 
3 Mecanismos fisiopatológicos relacionados com a resistência à insulina ou 
à hiperinsulinemia e à doença cardiovascular ( aterogênese) na síndrome 
metabólica e o diabetes tipo 2, 13 
4 Sistema renina-angiotensina e a síndrome metabólica, 17 
5 Obesidade, síndrome metabólica e doença cardiovascular, 21 
6 Diferenciação entre a resistência à insulina (RI) e o diabetes tipo 2, 25 
7 Relações entre síndrome metabólica, marcadores humorais de inflamação 
e disfunção endotelial, 29 
8 Estresse oxidativo e sua correlação com a resistência à insulina, o D M2 
e a doença cardiovascular (hipótese do solo comum modificada), 33 
9 Fisiopatologia da moléstia macrovascular diabética, 39 
Disfanção endotelial 
Dislipidemia 
Trombogênese 
10 Doença macrovascular específica, 43 
Diabetes e doença cardiovascular (DCV) 
Diabetes e acidente vascular cerebral (AVC) 
Diabetes e a moléstia arterial periférica (MAP) 
11 Estudos clínicos: diabetes mellitus tipo 2 e doença cardiovascular, 67 
12 Estratégias do tratamento do diabetes tipo 2 em pacientes coronariopatas, 71 
13 Diagnóstico da doença arterial coronariana (DAC) assintomática em 
pacientes com diabetes tipo 2, 79 
Referências, 93 
CAPÍTULO 1 
• • • 
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mo éstia macrovascu ar no 
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O diabetes mellitus do tipo 2 (DM2) atingiu proporções epidê-
micas em todo o globo. Projeções recentes do Diabetes Database, da 
Organização Mundial da Saúde, sugeriram que existem presente-
mente 180 milhões de indivíduos em todo o mundo com essa afec-
ção, e no Brasil a prevalência foi de 7 ,8% de uma amostra probabilís-
tica da população de 22.069.905 indivíduos rastreados para diabetes 
pelo Ministério da Saúde, em 2001, e atendidos pelo Serviço Único 
de Saúde (SUS). 
Ainda que os pacientes com DM2 possam apresentar certo nú-
mero de complicações microvasculares incapacitantes, eles têm maior 
probabilidade de falecer das complicações macrovasculares, que, por 
definição, são o acidente vascular cerebral (AVC), o infarto do mio-
cárdio (IM) e a moléstia arterial periférica (MAP). Ainda que o de-
senvolvimento acelerado da aterosclerose seja a principal explicação 
para a excessiva morbidade e mortalidade causada pelas várias formas 
clínicas da moléstia macrovascular no DM2, a esclerose da camada 
média das grandes artérias e a moléstia microvascular podem também 
ter algum papel na patogênese da moléstia vascular aterosclerótica. 
Assim, pacientes com DM2 têm um risco de mortalidade por 
doença cardiovascular (DCV) de 2 a 4 vezes maior do que os não 
diabéticos. A prevalência de diabetes e tolerância alterada à glicose 
CAPfTULO 1 
em 2.446 pacientes com eventos coronarianos agudos admitidos no 
Instituto do Coração (InCor), de 1997 a 1999, foi de 37% para os 
homens e 40% para as mulheres.Em relação à porcentagem de óbi-
tos, durante a internação dos pacientes, foi de 20,4% dos homens 
diabéticos, 14,6% daqueles com intolerância à glicose ( 11, 1 % dos 
não diabéticos), enquanto nas mulheres foi de 20,7% nas diabéti-
cas, 22,6% naquelas com intolerância à glicose (18,9% nas mulheres 
sem alterações no metabolismo da glicose) (dados não publicados). 
É interessante mencionar que o diabetes elimina a vantagem usual-
mente observada nas mulheres no que diz respeito ao risco de óbito 
na moléstia arterial coronariana, tendo sido observada uma mor-
talidade 5 a 8 vezes maior do que nas mulheres não diabéticas. 1 A 
observação desse risco excessivo de DCV levou recentemente a se 
considerar o DM2 como ''equivalente de risco cardiovasculares CV': 
indicando que portadores de diabetes têm um risco para eventos CV 
semelhante ao de indivíduos não diabéticos com DCV estabelecida 
(IM).2 Além disso, e possivelmente como parte desse alto risco para 
DCV, os pacientes com diabetes e formas mais leves de intolerância 
à glicose apresentam, com frequência, características da síndrome 
metabólica (SM), que aumentam acentuadamente o risco de DCV. 
O estudo de adultos no National Health and Nutrition Exami-
nation Survey-I (NHANES-I), de 1971 a 1975, e no NHANES-II, de 
1982 a 1984, que seguiu 9.639 indivíduos por 30 anos, revelou um 
declínio na mortalidade por DCV de 43,8% em homens não diabéti-
cos (p = 0,001), enquanto homens diabéticos mostraram aproxima-
damente 1/3 desse benefício (16,6%, p = 0,46). Mesmo as mulheres 
não diabéticas tiveram uma redução de 20,4%, ainda que não signi-
ficativa (p = 0,12), em contraste com o aumento de 10,7%, também 
não significativo (p = 0,76), nas mulheres diabéticas.3 
Numa revisão recente sobre o desenvolvimento de DCV em 
mulheres,4 foi chamada a atenção para o fato de que, com o diagnósti-
co de diabetes, o risco relativo de DCV aumentou mais nas mulheres 
do que nos homens. Assim, o risco para o infarto agudo do miocárdio 
(IAM) é 150% maior em mulheres diabéticas do que nas não diabéticas, 
enquanto apenas 50% maior em homens diabéticos do que nos não dia-
béticos, de acordo com os dados de Framingham, publicados em 1979. 
Enquanto as equações de Framingham fazem uma estimativa confiável 
2 
EPIDEMIOLOGIA DA MOLtSTIA MACROVASCULAR NO DIABETES TIPO 2 
do risco para a doença arterial coronariana (DAC) na população 
geral, elas podem subestimar, até pela metade, o risco para a mo-
léstia coronariana em diabéticos, a menos que calculadores de risco 
diabetes-específicos sejam utilizados, como o UK Prospective Study 
(UKPDS) Risk Engine for Type 2 Diabetes, que usam as variáveis 
disponíveis na rotina clínica, incluindo a duração do diabetes e a 
idade ao diagnóstico. 5 
O risco relativo maior de eventos ou mortalidade cardiovascular 
relacionados com o diabetes em mulheres em comparação aos ho-
mens tem sido demonstrado repetidamente, em diversas publicações. 
Em um estudo com enfermeiras (Nurses Health Study), com 121.046 
mulheres, que foram acompanhadas durante 20 anos, o risco de mor-
te por DAC nas com diabetes com mais de 15 anos de duração conhe-
cida foi similar ao observado em mulheres com DAC prévia e sem 
diabetes, e nas pacientes com longa duração do diabetes e história de 
DAC, a probabilidade de falecerem da doença coronariana era apro-
ximadamente 18 vezes maior do que naquelas sem nenhuma dessas 
condições ao entrarem no estudo. Essa investigação deu a primeira 
evidência documentada de um risco aumentado para os eventos car-
diovasculares antes do diagnóstico clínico de diabetes, precedendo 
o diagnóstico por mais de uma década e meia, com o nível de risco 
aumentando ainda mais após o diagnóstico de diabetes.6 
Em relação ao AVC, particularmente o isquêmico, o diabetes 
é também um fator de risco independente, em geral, presente em 
associação com outros fatores de risco (aterosclerótico), como hi-
pertensão arterial e dislipidemia. Cerca de 20% dos pacientes com 
AVC agudo observados em comunidade dinamarquesa eram diabé-
ticos, 85% do tipo 2. Por outro lado, hemorragia intracerebral foi 
muito menos frequente nos diabéticos. A recuperação nos diabéticos 
foi mais lenta e a mortalidade, mais elevada (26% vs. 17% nos não 
diabéticos).7 Um dos problemas relacionados ao prognóstico desses 
pacientes é a maior frequência da recorrência de AVC. 
Estudos populacionais mostraram, em um segmento de 1 O ou 
mais anos, que a mortalidade cerebrovascular foi de 2 a mais de 3 vezes 
maior em homens diabéticos do que nos não diabéticos, com idades 
variando de 35 a 64 anos, independentemente de idade, raça, pressão 
arterial, tabagismo e outros fatores de risco coronariano. Por outro 
3 
CAPfTULO 1 
lado, em enfermeiras acompanhadas por 8 anos (livres de moléstia 
cardiovacular (MCV), AVC e câncer ao entrar no estudo), o risco de 
AVC ajustado para a idade para as diabéticas vs. não diabéticas foi de 
4,1, similar para AVCs fatais e não fatais.8 
A MAP, que se caracteriza fundamentalmente por moléstia ate-
rosclerótica oclusiva das extremidades inferiores, é também um 
marcador de comprometimento aterotrombótico em outros leitos 
vasculares, particularmente coronariano e cerebrovascular. Dados 
do Framingham Heart Study revelaram que 20% dos pacientes com 
MAP têm diabetes, provavelmente subestimando a verdadeira pre-
valência, desde que mais pacientes com MAP são assintomáticos do 
que sintomáticos. Com efeito, tem sido reportado que, em pacientes 
com MAP, mais da metade é assintomática ou tem sintomas atípicos, 
cerca de 1/3 tem claudicação intermitente e os demais apresentam 
formas mais severas da moléstia, que se constituem em risco para 
amputação e são denominadas, em seu conjunto, isquemia crítica 
de extremidade. Ao utilizar a mensuração do índice tornozelo-bra-
quial, pela medida da pressão sistólica no tornozelo (artérias pedi os a 
dorsal e tibial posterior) e no braço (artéria braquial) com Doppler 
portátil e fazendo sua relação, pode-se avaliar quantitativamente o 
estado arterial das extremidades inferiores. Assim, com esse índice, 
mostrou-se que a prevalência de MAP em diabéticos com mais de 40 
anos foi de 20%. 
O diagnóstico da MAP tem importância clínica, que permi-
te identificar um paciente com alto risco de IM subsequente ou 
AVC, independentemente da presença ou não de sintomas de MAP. 
Além disso, mesmo com moléstia subclínica, estariam indicadas 
medidas preventivas para evitar, se possível, a isquemia aguda de 
extremidade.9 
Com os dados do Estudo Prospectivo de Diabetes do Reino 
Unido (UKPDS) para identificar os fatores de risco para o desen-
volvimento de MAP em DM2 recém-diagnosticados até 18 anos de-
pois, verificou-se que a hiperglicemia, acessada como HbAlc, esta-
va associada a um risco aumentado para MAP, independentemente 
de outros fatores de risco, incluindo idade, elevação da pressão arte-
rial sistólica, HDL-colesterol diminuído. Por outro lado, mostravam 
maior risco para MAP o tabagismo, MCV antecedente, neuropatia 
4 
EPIDEMIOLOGIA DA MOLtSTIA MACROVASCULAR NO DIABETES TIPO 2 
sensitiva periférica e retinopatia. Cada 1 % de aumento na HbAlc 
estava associado ao aumento do risco de MAP de 28% e a cada 10 
mmHg de elevação na pressão sistólica havia um aumento de 25% 
do risco. 10 Os diversos estudos prospectivos têm mostrado que a 
hiperglicemia estaria mais associada a MAP do que a DAC e diabé-
ticos com MAP comparados com aqueles sem MAP mostram arté-
rias coronarianas igualmente estenosadas, sugerindo que os efeitos 
da hiperglicemia na MAP poderiam ser influenciados por fatores 
locais. A glicemia poderia determinar placas ateroscleróticas rela-
tivamente estáveis, uma feição mais característica da MAP do que 
do IM.11 
5 
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1••········································································································ 1•••······································································································· 1•••······································································································· 1••········································································································ 1••········································································································ 1••········································································································ 1••········································································································ 1••········································································································ 1••········································································································ 1••········································································································ 1••········································································································ 1••········································································································ 1••········································································································ 1••········································································································ 1••········································································································ 1••········································································································ 1••········································································································ 1••········································································································ 1••········································································································ 1••········································································································ 1•••······································································································· 1••········································································································ 1•••······································································································· 1••········································································································ 1•••······································································································· 1••········································································································ 1••········································································································ 1•••······································································································· 1••········································································································ 1••········································································································ 1••········································································································ 1••········································································································ 1••········································································································1•••······································································································· 1••········································································································ 1••········································································································ 1••········································································································ 1•••······································································································· 1••········································································································ 1••········································································································ 1••········································································································ 1••········································································································ 1••········································································································ 1••········································································································ 1••········································································································ 1••········································································································ 1••········································································································ 1••········································································································ 1••········································································································ 1••········································································································ 1••········································································································ 1••········································································································ 1••········································································································ 1••········································································································ 1••········································································································ 1•••······································································································· 1••········································································································ 1••········································································································ 1••········································································································ 1••········································································································ 1••········································································································ 1••········································································································ 1••········································································································ 1••········································································································ 1••········································································································ 1••········································································································ 1••········································································································ 1••········································································································ 1••········································································································ 1••········································································································ 1••········································································································ 1••········································································································ 1••········································································································ 1•••······································································································· 1••········································································································ 1••········································································································ 1••········································································································ 1••········································································································ 1••········································································································ 1••········································································································ 1••········································································································ 1••········································································································ 1••········································································································ 1•••······································································································· 1•••······································································································· 1••········································································································ 1•••······································································································· 1••········································································································ 1•••······································································································· 1•••······································································································· 1•••······································································································· 1••········································································································ 1••········································································································ 1••········································································································ 1••········································································································ 1••········································································································ 1••········································································································ 1••········································································································ 1••········································································································ 1••········································································································ 1••········································································································ 1••········································································································ 1••········································································································ 1••········································································································ 1••········································································································ 1••········································································································ 1••········································································································ 1••········································································································1••········································································································ 1••········································································································ 1••········································································································ 1••········································································································ 1••········································································································ 1••········································································································ 1••········································································································ ·----------------------------------------------------------------------------------------------------------
CAPÍTULO 2 
,,,,,,,,ín rome meta ó ica 
e oença macrovascu ar 
O conjunto de fatores de risco metabólicos e fisiológicos relacionados 
con1 a doença cardiovascular DCV tem sido definido como síndrome de 
resistência à insulina, síndrome X, síndrome metabólica (SM) e síndrome 
dismetabólica cardiovascular, entre outras denominações. As definições 
propostas para a SM têm diferido com respeito a seus componentes e o 
nível de corte destes. Entretanto, as recentes tentativas para definir a SM 
têm incluído as 5 condições: obesidade abdominal, hipertrigliceridemia, 
baixos níveis de HD L-colesterol, hipertensão arterial e resistência à insu-
lina. A definição mais empregada atualmente é a proposta pelo National 
Cholesterol Education Program (NCEP), 12 indicada na Tabela 2-1. 
Característica 
Obesidade abdominal: circunferência abdominal 
(cintura em cm) 
Homens 
Mulheres 
Triglicérides (mg/dl) 
HDL- colesterol (mg/dl) 
Homens 
Mulheres 
Critério** 
>102 
> 88 
~ 150 
>40 
>50 
(continua) 
CAPfTULO 2 
Tabela 2·1 Critérios diagnósticos da síndrome metabólica* (continuação) 
Pressão arterial (mm/Hg) 
Glicemia de jejum (mg/dl) 
*Segundo o National Cholesterol Education Program.12 
**O diagnóstico requer 3 das 5 características clínicas. 
~ 130/85 
~ 110 
Essa proposta do NCEP para a definição da SM é clinicamente 
prática, define um grupo de pacientes com elevado risco de DCV e 
não necessita da medida da resistência à insulina nem dos marcado-
res inflamatórios. 
Para avaliar adultos com SM, participantes do NHANES-III 
(Third National Health and Nutrition Examination Survey), conduzi-
do pelo National Center of Health Statistics, Centers of Disease Con-
trol and Prevention ( 1988-1994), do governo dos Estados Unidos, que 
tinham mais de 50 anos (idade média± EPM: 64,3 ± 0,3 anos; 45,2°/o 
do sexo masculino e IMC: 27,4 ± 0,3 kg/m2), foram categorizados 
para a presença da SM, definida de acordo com o NCEP, com e 
sem diabetes, por Alexander et al. 13 Eles observaram um aumen-
to progressivo na prevalência da SM com a piora da tolerância à 
glicose, variando de 26% naqueles com glicemia normal de jejum 
(57% da população) para 33% nos indivíduos com tolerância alte-
rada à glicose (13,7% da população), a prevalência sendo de 71 % 
naqueles com glicemia alterada de jejum ( 12,3% da população 
estudada) e chegando a 86% nos indivíduos com diabetes estabe-
lecido ( 17% da população). Portanto, concluíram ser a SM muito 
comum na população norte-americana acima dos 50 anos, com o 
achado em torno de 43,5%. Em contraste, diabéticos sem a SM foi 
pouco prevalente nessa população (cerca de 13% dos diabéticos 
não preencheram os critérios do NCEP para a SM). Assim, indi-
víduos nesse grupo etário sem SM, independentemente do estado 
diabético, tinham a menor prevalência de doença coronária (8,7% 
sem diabetes vs. 7,5% com diabetes). Os indivíduos com SM e sem 
diabetes tinham uma prevalência de DAC de 13,9%, enquanto 
aqueles com ambos, SM e diabetes, mostravam a maior prevalên-
cia (19,2%). Para concluir, esse importante estudo mostrou que o 
excesso de prevalência de moléstia coronariana entre os diabéticos 
estava no grupo com ambos, diabetes e SM. 
8 
Sf NDROME METABÓLlCA E DOENÇA MACROVASCULAR 
Estudos populacionais também mostraram a associação entre a 
SM com IM e AVC, como o de Ninomiya et al., que avaliou 10.357 
indivíduos do NHANES-III para os 5 critérios da SM, de acordo 
com o NCEP-III, indicando que a SM estava relacionada significa-
tivamente, na análise multivariada, com o IM [OR (''odds ratio'' ou 
razão de chances)= 2,01],AVC (OR = 2,16) e IM/AVC (OR = 2,05). 
A SM foi significativamente associada ao IM/AVC nos 2 sexos. En-
tre os componentes da SM, a glicemia de jejum~ 110 mg/dl (OR = 
1,30), o HDL-colesterol baixo (OR = 1,35), a hipertensão (OR = 1,44) 
e a hipertrigliceridemia (OR = 1,66) se mostraram independente e 
significativamente relacionados com o IM/ A VC.14 Esses achados são 
importantes porque a hipertrigliceridemia nem sempre é considera-
da um importante contribuidor de risco de DAC e que pode ser uma 
das alterações mais precoces presentes na SM. Outro achado signi-
ficativo desse estudo foi o risco similar do IM/ AVC nos indivíduos 
com SM independente ou não de história de diabetes, o que enfatiza 
o ponto de que o risco de eventos cardiovasculares está aumentado 
independentemente de hiperglicemia incidente. Um achado nesse es-
tudo foi a não correlação entre a circunferência abdominal e o risco 
para IM/AVC. Considerando que a obesidade do tronco (indicativa 
do aumento do tecido adiposo visceral) tem sido vista como uma 
anormalidade central e característica da SM e que estudos anteriores 
mostraram forte correlação, essa falta de associação levanta uma sé-
rie de possibilidades. Primeiro, seria concebível que a circunferência 
abdominal seja um melhor indicador nos indivíduos jovens e consi-
derando que os pacientes no estudo de Ninomiya et al. com IM/ AVC 
são consideravelmente mais velhos (69 vs. 47 anos), a circunferência 
abdominal não apareceu como um preditor independente, sobretudo 
quando outros componentes da SM foram incluídos na análise dos 
dados. Como sugerido pelos autores, seria também possível que o 
efeito da medida da cintura abdominal estivesse diluído por causa do 
impacto mais intenso de outros componentes da SM, como a hiper-
trigliceridemia. Finalmente, seria concebível que circunferência ab-
dominal, ainda que geralmente aceita, nem sempre seja uma medida 
acurada do aumento da adiposidade visceral. 
Por outro lado, as definições da SM da Organização Mundial da 
Saúde e do NCEP - a primeira com foco na resistência à insulina 
9 
CAPfTULO 2 
(hiperinsulinemia) - mostraram que havia uma probabilidade de 5 a 
9 vezes de desenvolvimento do diabetes durante o acompanhamen-
to de uma coorte de 1.005 homens finlandeses, de 42-60 anos, sem 
DCV, diabetes e câncer, acompanhados por 4 anos (Kuopio Ische-
mic Heart Disease Risk Factor Study). Outro estudo populacional 
recente, realizado em Beaver Dam, Wisconsin, Estados Unidos, com 
4.926 indivíduos, com idades de 43 a 86 anos, acompanhados por 
2-5 anos, mostrou que o risco de MCV incidente se elevava com o 
número de componentes da SM, tendo aumentado mais de 5 vezes 
naqueles indivíduos com 4 ou mais componentes ( 14,9%) quando 
comparados com os que mostravam apenas 1 componente (2,5%). 
Daqueles com 1 componente foi observado o desenvolvimento de 
diabetes em 1,1 % em 5 anos, enquanto o diabetes foi diagnosticado 
em 17 ,9% dos indivíduos com 4 ou mais componentes da SM. 16 Esses 
dados são clinicamente importantes, pois enfatizam que o risco de 
MCV e diabetes aumenta de um modo incremental com os vários 
componentes da SM. 
Uma avaliação de 64 diabéticos admitidos no InCor, entre 2000 
e 2001, submetidos à arteriografia coronária e com DAC e idade de 
58,8 ± 0,8 anos (média ± DP), sendo 48,7% homens, IMC de 28,9 ± 
4,7 kg/m2, colesterol total de 219 ± 55 mg/dl, HDL-colesterol de 38 
± 13 mg/dl, LDL-colesterol de 146 ± 51 mg/dl, triglicérides de 172 ± 
92 mg/dl e glicemia de jejum de 162 ± 75 mg/dl, mostrou que 45,3%referiam prévio diagnóstico do DAC, 89,l % tinham hipertensão ar-
terial, 64,l %, dislipidemia, 42,l % eram obesos e 21,9% referiam ser 
fumantes. Apenas 2 diabéticos (3%) não apresentavam nenhum dos 
fatores de risco citados, 20% tinham apenas um fator de risco (prin-
cipalmente a hipertensão arterial), 42% dos diabéticos com DAC 
apresentavam 2 fatores de risco (mais frequentemente hipertensão 
e dislipidemia), 32% mostravam ser portadores de 3 fatores de risco 
(principalmente hipertensão+ dislipidemia +obesidade/tabagismo) 
e, finalmente, apenas 2 pacientes (3%) tinham os 4 fatores de risco 
(hipertensão+ dislipidemia +obesidade+ tabagismo). De modo ge-
ral, houve uma boa correlação entre extensão e gravidade da DAC e 
o número de fatores de risco (dados não publicados). 
Entretanto, a forte associação entre a SM e a DCV poderia não 
ser universal. Sabe-se que, embora os afro-americanos tenham maior 
10 
Sf NDROME METABÓLlCA E DOENÇA MACROVASCULAR 
prevalência da SM, seu risco de IM não está aumentado proporcional-
mente. Dados recentes do The Strong Heart Study, com 2.283 índios 
norte-americanos não diabéticos e sem DCV na entrada do estudo, 
dos quais 35% tinham a SM, com acompanhamento por aproxima-
damente 8 anos para observação da incidência da DCV, mostraram 
que 7,9% desenvolveram MCV. Ainda que os vários componentes 
da SM e o risco para diabetes aumentaram através dos tereis da re-
sistência à insulina (avaliada pelo Homeostasis Model Assessment: 
HOMA-IR), o risco de DCV não aumentou como uma função do 
HOMA-IR basal ou SM definida pelo NCEP, mas os fatores de risco 
cardiovascular individuais foram preditivos de subsequente DCV.17 
Os resultados desse estudo enfatizam a importância de acessar os 
atributos de risco da SM nas várias populações, já que o risco pode 
ser muito elevado em algumas, como nos indivíduos do sul da Ásia 
que migraram para as áreas urbanas da Grã-Bretanha, ou não o ser 
em outras, como o observado nos índios norte-americanos. 
A associação da SM com a DCV levanta importantes questões 
relativamente aos processos fisiopatológicos subjacentes. Aceita-se, 
de uma maneira geral, que a resistência à insulina (RI) é a anorma-
lidade primária que precede a maioria das alterações metabólicas e 
outras anormalidades vistas na SM e contribui para sua ocorrência. 
11 
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CAPÍTULO 3 
ecanismos isio ato ó icos 
re aciona os com a resistência 
\ . . \ . . . . 
a 1nsu 1na ou a 1 er1nsu 1nem1a 
\ . 
e a oença car 1ovascu ar 
atero---ênese na sín rome 
meta ó ica e o ia etes ti o 
O termo RI é empregado para indicar a incapacidade da insu-
lina em promover a homeostase normal da glicose. Essa diminuída 
ação da insulina demanda a presença de concentrações de insulina 
maiores do que as observadas em condições normais, ou seja, hipe-
rinsulinemia para manter a normoglicemia e a utilização normal da 
glicose nos tecidos-alvo. Assim, o termo RI implica o efeito inade-
quado da insulina no metabolismo da glicose, mas não leva em con-
sideração outros aspectos da ação da insulina, considerando que é o 
hormônio anabólico mais potente, que exerce uma multiplicidade de 
efeitos no metabolismo lipídico e proteico, no transporte de íons e 
aminoácidos, no ciclo celular e na proliferação, diferenciação e sín -
tese do óxido nítrico. 
CAPfTULO 3 
Aceita-se atualmente que a presença da hiperinsulinemia com-
pensatória pode estimular certos aspectos da ação da insulina em vá-
rios tecidos e células, assim sendo, foi introduzido o conceito de ''RI 
seletivà: Foi demonstrada, em biópsias de músculo de portadores de 
DM2 e de obesos não diabéticos (submetidos a um clampeuglicêmi-
co hiperinsulinêmico com um exercício de moderada intensidade), 18 
uma redução acentuada, mais nos portadores de DM2, da fosforila-
ção do substrato do receptor de insulina (IRS)-1 e -2 e ativação da 
fosfatidilinositol 3-quinase (PI3-quinase ), que é absolutamente ne-
cessária para mediar os efeitos metabólicos da insulina. Em adição 
aos bem conhecidos efeitos metabólicos da insulina, tais como no 
transporte da glicose, na síntese do glicogênio e no metabolismo lipí-
dico, a via da PI3-quinase tem ação mediadora dos efeitos vasodila-
tador e anti-inflamatório da insulina via ativação da sintase do óxido 
nítrico. Por outro lado, a ativação da via da MAP (mitogen activated 
protein) quinase, que contribui para os efeitos nuclear e mitogênico 
da insulina, foi normal nos obesos e diabéticos. 18 A preservação da 
via da MAP quinas e, com a promoção dos efeitos mitogênicos, leva 
ao crescimento e à proliferação das células endoteliais, 19 deslocando, 
assim, o equilíbrio em favor das ações aterogênicas da insulina. 
Em concentrações fisiológicas, a insulina tem ação vasodilata-
dora e anti-inflamatória que é mediada, pelo menos em parte, pela 
expressão e atividade da sintase endotelial do óxido nítrico (eNOS), 
resultando no aumento da produção e liberação do óxido nítrico 
(NO) e na inibição da transcrição do fator nuclear-kB (NF-kB).20 Es-
sas ações são mediadas pela via PI3-quinase em que o Akt, um alvo 
distal da PI3-quinase, vai promover a fosforilação do eNOS e sua 
ativação. 21 
Assim, a biodisponibilidade de NO representa um marcador-
chave da saúde vascular: o NO causa a vasodilatação, por ativar a 
guanilil ciclase na musculatura lisa subjacente à célula endotelial e 
protege o vaso de lesão endógena - aterosclerose -, por mediar os 
sinais vasculares que previnem a interação de plaquetas e leucócitos 
com a parede vascular e inibir a proliferação e migração da célula 
muscular lisa. Por outro lado, a perda do NO derivado do endotélio 
permite o aumento da atividade do fator nuclear de transcrição pró-
inflamatório kB (NF-kB), resultando na expressão de moléculas de 
14 
MECANlSMOS FlSlOPATOLÓGlCOS RELAClONADOS COM A 
RESlSTtNClA À lNSULlNA ... 
adesão dos leucócitos e produção de quimocinas e citocinas. Essas 
ações promovem a migração de monócitos e células musculares lisas 
para a formação de macrófagos espumosos, caracterizando as alte-
rações morfológicas iniciais da aterosclerose.22 Portanto, a disfunção 
endotelial, representada pelo comprometimento endotélio-depen-
dente da vasodilatação NO-mediada, ocorre na resistência à insulina 
e no diabetes, por redução da biodisponibilidade do NO que estaria 
na predisposição aterogênica dessas condições. A biodisponibilidade 
de NO reflete o balanço entre sua produção via NOS e sua degrada-
ção, particularmente por radicais livres derivados do oxigênio, que 
será discutido posteriormente. 
Diversos estudos clínicos também enfatizaram que a SM é uma 
condição pró-inflamatória, pela associação positiva entre seus com-
ponentes e os marcadores da resposta da fase aguda, incluindo pro-
teína e-reativa, fibrinogênio, interleucina-6 e contagemde glóbulos 
brancos. Níveis elevados desses marcadores inflamatórios também 
são preditores de desenvolvimento do diabetes do tipo 2.23 Além 
disso, a todos os níveis de severidade da SM, a proteína e-reativa 
acrescenta informação prognóstica no risco subsequente de eventos 
cardiovasculares. 24 
Além da proteína e-reativa, também existem evidências de que 
diversos fatores aterotrombóticos estão aumentados na SM, incluin-
do os níveis elevados do inibidor-1 do ativador do plasminogênio 
(PAI-1), fibrinogênio sérico, fator Von Willebrand, fator VII e trom-
bina, bem como o aumento da ativação e agregação das plaquetas.22 
Todas as mencionadas anormalidades levam ao risco aumentado de 
nev, especialmente a DAe. 
Essas observações, em conjunto com a pesquisa básica nos me-
canismos inflamatórios da SM (e o DM2) e da disfunção vascular, 
sugerem fortemente que a RI e a aterosclerose têm uma base infla-
, . 
mataria comum. 
Por outro lado, a insulina em concentrações fisiológicas, que in-
duz a liberação do NO, leva à supressão do NF-kB intranuclear e à 
redução da proteína e-reativa e de moléculas de adesão, em células 
endoteliais aórticas humanas. Esses efeitos da insulina são rápidos, 
profundamente anti-inflamatórios e provavelmente antiaterogênicos 
a longo prazo. Se aterosclerose é reconhecida como uma inflamação 
15 
CAPfTULO 3 
da parede arterial, a ação do NF-kB tem sido considerada como cen-
tral para a aterogênese por induzir a transcrição de moléculas pró-
inflamatórias. Com efeito, a expressão de NF-kB nas placas ateros-
cleróticas tem sido consistente. 20 O uso de insulina, com sucesso, no 
infarto agudo do miocárdio em diabéticos e não diabéticos, poderia 
refletir a acentuada propriedade anti-inflamatória da insulina e seu 
potencial antitrombótico. Deve-se também mencionar as ações anti-
inflamatórias com efeitos inibitórios no fator de transcrição NF-kB 
da classe das tiazolidinedionas. 
16 
CAPÍTULO 4 
~ , sistema renina-an iotensina 
e a sín"""rome meta....,.ó ica 
A angiotensina II (AII), o principal efetor peptídico do sistema 
renina-angiotensina, regula o tônus vasomotor, a pressão arterial e a 
estrutura cardiovascular, em grande parte por meio da ativação da 
proteína G-acoplada ao receptor ATl. Evidências consideráveis suge-
rem que a AII pode também modular as ações da insulina.25 As com-
plexas interações celulares do sistema renina-angiotensina (SRA) e 
a sinalização da insulina incluem, após a ligação com os respectivos 
receptores, as vias de transdução de sinal comuns, as vias da PI3-
quinase e MAP-quinase e a fosforilação dos substratos do receptor 
da insulina (IRS)-1 e 2. A fosforilação do IRS-1 e IRS-2 mediada pelo 
receptor da insulina ativa, como já indicado, as vias da PI3-quinase, 
enquanto a ativação mediada pela AII inibe essa via. Assim, a ativa-
ção do SRA pode inibir as ações metabólicas da insulina pela PI3-
quinase, mas sinergisticamente promover os efeitos proliferativos 
pela MAP-quinase. 
Adicionalmente, tanto a hiperglicemia como a insulina ativam o 
SRA por aumentar a expressão do angiotensinogênio,AII e o receptor 
ATl, que, em conjunto, poderão contribuir para o desenvolvimento 
da hipertensão nos pacientes com RI. Além disso, o SRA tem sido 
implicado na patogênese da ruptura da placa aterosclerótica, com 
aumento da enzima de conversão da angiotensina e da atividade da 
CAPfTULO 4 
AII observada primariamente nos macrófagos nas lesões ateroscleró-
ticas. Quando a AII atua por meio dos receptores ATl, é um potente 
estímulo para a geração das espécies reativas do oxigênio nos vasos 
sanguíneos que é ainda acentuada em estados hiperglicêmicos. Esse 
aumento do estresse oxidativo pode provocar disfunção endotelial, 
inflamação, hipertrofia da musculatura lisa e remodelação vascular. 
A AII também contribui para a f armação da placa ao promover o re-
crutamento de macrófagos e linfócitos T pela geração de moléculas 
de adesão e citocinas; inibir a atividade fibrinolítica pelo aumento da 
expressão do PAI-1; induzir a remodelação da parede arterial media-
da pelo crescimento, pela migração e proliferação da célula muscular 
lisa; e alterar a composição da matriz extracelular. 
O estresse oxidativo impulsionado pelo SRA tem sido proposto 
como um estímulo para a f armação dos produtos finais de glicação, 
que têm papel fundamental na patogênese da lesão vascular nos es-
tados hiperglicêmicos mediados, em parte, pela geração de espécies 
reativas de oxigênio. 26 
Há indícios de que a ativação do SRA e sua interação com a sina-
lização da insulina levou à exploração do potencial terapêutico da ini-
bição do SRA no tratamento da SM. Assim, se mostrou que a inibição 
da enzima de conversão da angiotensina melhorou a sensibilidade à 
insulina e o controle glicêmico em diabéticos, havendo uma redu-
ção significativa na incidência de casos novos de diabetes do tipo 2, 
de eventos cardiovasculares e nas complicações do diabetes. 27-29 
O mecanismo pelo qual os inibidores da enzima de conversão da 
angiotensina melhoram a sensibilidade à insulina parece ser devido, 
em parte, ao aumento da captação da glicose no músculo esquelético 
pelo aumento da síntese e translocação para a superfície celular do 
GLUT 4 (transportador 4 da glicose), um efeito determinado pela 
ativação da fosforilação da tirosina do IRS-1 e pelo aumento da bra-
dicinina e NO. 26 
Os bloqueadores do receptor da angiotensina II (ARBs: Angio-
tensin II Receptor Blockers) se ligam competitivamente ao receptor 
ATl, com elevada afinidade e seletividade e baixa dissociação. Ore-
ceptor ATl está presente em muitos tecidos e órgãos, inclusive co-
ração, vasos sanguíneos, rins e adipócitos, enquanto o receptor AT2 
tem níveis baixos de expressão após o nascimento, e a maioria dos 
18 
O SISTEMA RENINA-ANGIOTENSINA E A SfNDROME METABÓLICA 
efeitos fisiológicos e fisiopatológicos da AII parecem ser mediados 
através do receptor AT 1. 
A regressão significativa da hipertrofia ventricular esquerda 
de pacientes hipertensos essenciais com ARBs levantou a possibili-
dade de que esses medicamentos poderiam ser superiores a outros 
agentes com hipertrofia ventricular esquerda. Com efeito, no estudo 
Losartan Intervention for Endpoint Reduction (LIFE), de pacientes 
com hipertensão arterial e hipertrofia ventricular esquerda, o ARB 
losartan reduziu os eventos cardiovasculares em 13% e a incidência 
de novos diabéticos do tipo 2 em 25% em comparação com o beta-
bloqueador atenolol.3º'31 O mesmo foi observado com outros ARBs 
(em comparação com diversos medicamentos anti-hipertensivos), 
que parecem ser tão eficientes como os inibidores das enzimas de 
conversão da angiotensina em reduzir os eventos cardiovasculares e 
prevenir o desenvolvimento de novos casos de diabetes em pacientes 
de alto risco. Assim como para os inibidores da enzima de conver-
são da angiotensina, os estudos com os ARB têm sido convincentes, 
sugerindo o papel terapêutico desses últimos nos pacientes com a 
SM, pela ação do metabolismo da glicose. Além disso, a disfunção 
endotelial, que é preditiva da futura morbidade e mortalidade car-
diovascular, pode ser revertida pelo bloqueio do receptor ATl a cur-
to e a longo prazos. Como seria de se esperar, o efeito cardioprotetor 
está associado ao aumento da biodisponibilidade do NO, à redução 
do estresse oxidativo e à modulação anti-inflamatória da superfície 
celular e de moléculas de adesão circulantes. 
Os ARBs parecem ser equivalentes aos inibidores da enzima de 
conversão da angiotensina para o tratamento da insuficiência cardí-
aca e podem prover proteção superior de órgãos, como a vasculatura 
em geral, o coração, o cérebro e os rins, além de sua potência anti-
hipertensiva. 26 Estudos clínicos recentes têm indicado que os ARBs 
têm um efeito benéfico que vai além da redução da pressão arterial. 
19 
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