Estratificação Cardiovascular em Pacientes com Diabetes

Estratificação Cardiovascular em Pacientes com Diabetes
Apresentação: Elias Gouvêa Serviço de Cardiologia: Hospital Rios D`Or 10.Out.2009

Conceitos Emergentes Proteção Cardiovascular

A placa ...

Diabetes Aumenta o Risco de Ruptura da Placa e Trombose como Causa de IAM
Agregação Plaquetas Fibrinogenio vWF F VII F VIII Diabetes Increases Risk of Coronary Plaque Disruption and Thrombosis: Cause of Myocardial Infarction This slide depicts the factors that participate in the causation of myocardial infarction. Diabetes increases plaque formation with the development of a vulnerable plaque prone to disruption. The increased sympathetic tone due to autonomic neuropathy in diabetic patients may predispose the patient to plaque disruption. Patients with diabetes have increased platelet aggregation and are prothrombotic because of an increase in clotting factors and fibrinogen. Elevated levels of plasminogen activator inhibitor 1 (PAI-1) create a setting for clot formation on the basis of impaired fibrinolysis. These factors conspiring together increase the risk for thrombosis should coronary plaque disruption occur. Artéria Coronária PAI-1 TPA PGI2 Trombo Formação Placa Ruptura da Placa Tonus Simpatico

Síndrome Metabolica x Doença Cardiovascular x DM 2
LDL-C Elevado Síndrome Metabólica DM2 Metabolic syndrome increases risk for CHD and type 2 diabetes The NCEP has traditionally focused on high low-density lipoprotein cholesterol (LDL-C) as a risk factor for coronary heart disease (CHD). In the NCEP Adult Treatment Panel III (ATP III) recommendations published in JAMA in 2001, the NCEP suggested that the metabolic syndrome might independently predict the development of both type 2 diabetes and CHD. Reference: Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285: Doença Coronariana Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:

Doença vascular periférica
Custos com Hospitalização por Complicações Crônicas da Diabetes nos EUA Doença Oftalmológica Outras Doença neurológica DAC relaciona- se a 64% dos custos totais Custo total de 12 bilhões USD Doença renal Doença vascular periférica Hospitalization Costs for Chronic Complications of Diabetes in the US These data from the ADA emphasize that 1) type 2 diabetes is extremely costly, and 2) cardiovascular disease constitutes 64% of total costs. Reference: American Diabetes Association. Economic Consequences of Diabetes Mellitus in the US in Alexandria, Va: American Diabetes Association, 1998:1-14. Doença cardiovascular American Diabetes Association. Economic Consequences of Diabetes Mellitus in the US in Alexandria, VA: American Diabetes Association, 1998:1-14.

Mortalidade em Pessoas com Diabetes Causas de Morte
% das mortes Mortality in People with Diabetes: Causes of Death Among people with diabetes, about two-thirds of deaths are due to cardiovascular disease. Approximately 40% are due to ischemic heart disease, about 15% are due to other heart disease, principally congestive heart failure, and about 10% are due to stroke. These data suggest that therapies to treat diabetes should be evaluated at least in part by their effects on cardiovascular disease. Reference: Geiss LS, Herman H, Smith PJ. Mortality in non-insulin-dependent diabetes. In: National Diabetes Data Group. Diabetes in America. 2nd ed. Bethesda, Md: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, 1995: DAC Outras cardiov. Diabetes Cancer AVE Infecção Outras Geiss LS, et al. In: Diabetes in America. 2nd ed

Mortes Cardiovasculares por ano
Estudo Framingham : DM e Mortalidade por Doença Cardiovascular Follow-up de 20 anos 17 17 DM Não-DM Mortes Cardiovasculares por ano por 1000 Pessoas Framingham Study: DM and CHD Mortality: 20-Year Follow-up In this 20-year follow-up from the Framingham Heart Study, coronary heart disease (CHD) death is increased twofold in diabetic men relative to nondiabetic men. Among women, there is an even greater excess in CHD death, fourfold higher in diabetic women compared with nondiabetic women, which may in part be due to more adverse cardiovascular risk factors, particularly low high-density lipoprotein (HDL) cholesterol, in diabetic women. In addition, this slide shows that the absolute CHD death rate in diabetic women is the same as in diabetic men, suggesting that diabetes leads to the abolishment of the female protection against CHD. However, most studies show a diminution but not complete abolishment of the sex difference between diabetic women and diabetic men. Reference: Kannel WB, McGee DL. Diabetes and cardiovascular disease: the Framingham study. JAMA 1979;241: 8 4 Homens Mulheres Kannel WB, McGee DL. JAMA. 1979;241:

Mortalidade Por Doença Cardíaca em Homens e mulheres com ou sem Diabetes (US)
29.9 Diabetes Sem Diabetes 23.0 19.2 Mortalidade por Pessoas-ano* Mortality Due to Heart Disease in Men and Women with or without Diabetes (US) Individuals categorized as diabetics or nondiabetics on the basis of a medical history interview in the first National Health and Nutrition Examination Survey (NHANES I; ) were followed up for mortality through Both heart disease mortality and ischemic heart disease mortality were much higher in diabetic subjects, men and women, than in people without diabetes. Reference: Gu K, Cowie CC, Harris MI. Mortality in adults with and without diabetes in a national cohort of the U.S. population, Diabetes Care 1998;21: 11.5 11.0 6.3 7.1 3.6 Homens Mulheres Mulheres Homens Todas as Doenças cardiovasculares Doença Coronariana *Age-adjusted Adapted from Gu K, et al. Diabetes Care. 1998;21:

Probabilidade de Morte por DAC em Pacientes com DMNID e em Não diabéticos, com ou sem antecedente de IAM 100 80 60 Sobrevida (%) Probability of Death From CHD in Patients With NIDDM and in Nondiabetic Patients, With and Without Prior MI The treatment of cardiovascular risk factors in patients with diabetes is controversial, with some investigators suggesting that such patients should be treated as though they had established coronary heart disease (CHD). To determine whether diabetic patients who have not had myocardial infarctions (MIs) should be treated as aggressively for cardiovascular risk factors as diabetic patients who have had MIs, Haffner and colleagues compared the 7-year incidence of MI (both fatal and nonfatal) among 1,378 nondiabetic subjects with the MI incidence among 1,059 subjects with non-insulin-dependent diabetes mellitus (NIDDM) in a Finnish population-based study. The probability of death from CHD was estimated among diabetic and nondiabetic subjects, with and without prior MI. As this slide shows, the probability of death from CHD was highest among diabetic subjects with prior MI and was lowest among nondiabetic subjects without prior MI. Diabetic subjects without prior MI and nondiabetic subjects with prior MI had intermediate survival rates as well as similar outcomes. These findings suggest that cardiovascular risk factors should be treated in diabetic patients as aggressively as in nondiabetic patients with prior MI. References: Haffner SM. The Scandinavian Simvastatin Survival Study (4S) subgroup analysis of diabetic subjects: implications for the prevention of coronary heart disease. Diabetes Care. 1997;20:469–471. Haffner SM, Lehto S, Ronnemaa T, Pyörälä K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med. 1998;339:229–234. 40 Não diabeticos sem IAM prévio Diabeticos sem IAM prévio Não diabeticos com IAM prévio Diabeticos com IAM prévio 20 1 2 3 4 5 6 7 8 Anos Kaplan-Meier estimates Haffner SM et al. N Engl J Med 1998;339:229–234..

Sobrevida Pos IAM em Diabéticos e Não diabéticos - Homens e mulheres: Minnesota Heart Survey
100 80 60 40 100 80 60 40 Sem diabetes Sem diabetes n=1628 n=568 Sobrevidal (%) Survival Post-MI in Diabetic and Nondiabetic Men and Women: Minnesota Heart Survey In the Minnesota Heart Study, the case fatality rate after admission to the coronary care unit over 5 years was significantly higher in diabetic men than in nondiabetic men, and also in diabetic women relative to nondiabetic women. This analysis suggests that the case fatality rate may be higher in diabetic women than in diabetic men. Reference: Sprafka JM, Burke GL, Folsom AR, McGovern PG, Hahn LP. Trends in prevalence of diabetes mellitus in patients with myocardial infarction and effect of diabetes on survival: the Minnesota Heart Survey. Diabetes Care 1991;14: Diabetes Survival (%) n=228 Diabetes n=156 20 40 60 80 20 40 60 80 Meses pós IAM Meses pós IAM Adapted from Sprafka JM, et al. Diabetes Care. 1991;14:

Eventos Coronarianos Maiores no 4S -Pacientes com ou sem Diabetes pela História (n=202)
1.0 0.9 0.8 0.7 0.6 0.5 Proporção sem evento Cardiovascular Maior Major Coronary Events in 4S Patients with or without Diabetes by History (n=202) The Kaplan-Meier curve for major coronary events in previously diagnosed diabetics in 4S (n=202) shows that diabetics treated with simvastatin had a somewhat better prognosis than nondiabetics. At least in diabetic patients with previous CHD and high LDL cholesterol, statin therapy is an extremely effective therapy, perhaps equivalent to eliminating the excess risk associated with CHD. Reference: Pyörälä K, Pedersen TR, Kjekshus J, Faergeman O, Olsson AG, Thorgeirsson G, Scandinavian Simvastatin Survival Study (4S) Group. Cholesterol lowering with simvastatin improves prognosis of diabetic patients with coronary heart disease: a subgroup analysis of the Scandinavian Simvastatin Survival Study (4S). Diabetes Care 1997;20: Diabetes pela Hx, sinvastatin Diabetes pela Hx, placebo Sem diabetes pela Hx, sinvastatin SEm diabetes pela Hx, placebo P=0.002 P=0.0001 1 2 3 4 5 6 Anos Desde a Randomização Adapted from Pyörälä et al. Diabetes Care 1997;20:

Frequência do HDL-C baixo Comparado com Outros Fatores de Risco em Homens com DAC Prematura
Casos Controles (n = 321) Fator de risco (n = 601) Não adjustados Ajustados Tabagismo 29% 67%* — HDL-C  35 mg/dL 19% 63%* 57%* Hipertensão (PA  150/90) 21% 41%* — LDL-C  160 mg/dL 26% 26% 34%* Diabetes mellitus 1% 12%* — Frequency of Low HDL-C Compared With Other Risk Factors in Men With Premature CHD Genest and colleagues assessed the prevalence of modifiable cardiovascular risk factors in 321 men aged < 60 years with premature coronary heart disease (CHD), using subjects in the Framingham Offspring Study (FOS) population (i.e., 601 men with no evidence of cardiovascular disease) as a comparison group. This slide lists the clinical characteristics of the subjects in this study, compared with those of the FOS controls. The prevalence of high-density lipoprotein cholesterol (HDL-C) levels < 35 mg/dL was threefold greater (57% versus 19%) in men with premature CHD than in healthy controls. This threefold increase in low HDL-C values among CHD patients (cases) was substantially greater than the 1.3-fold increase (34% versus 26%) in the frequency of low-density lipoprotein cholesterol (LDL-C) levels  160 mg/dL in cases compared with controls. References Genest JJ, McNamara JR, Salem DN, Schaefer EJ. Prevalence of risk factors in men with premature coronary artery disease. Am J Cardiol. 1991;67:1185–1189. Wilson PW, Christiansen JC, Anderson KM, Kannel WB. Impact of national guidelines for cholesterol risk factor screening: the Framingham Offspring Study. JAMA. 1989;262:41–44. *Significantly different from controls (P < 0.001) Genest JJ et al. Am J Cardiol 1991;67:1185–1189

Mudança na Mortalidade por DAC ao longo do tempo em Pacientes com e sem Diabetes
Diabeticos Não diabeticos 18 17 16 Men (NHANES I, 1971–75) Men (NHEFS, 1982–84) Women (NHANES I, 1971–75) Women (NHEFS, 1982–84) 14.2 14 12 por pessoas-ano Mortalidade (%) 10 Changing Mortality Rates Over Time for CHD in Patients With and Without Diabetes Although mortality from coronary heart disease (CHD) has shown a marked decline in the United States during the past 30 years, it was unclear whether this decline applied to patients with diabetes. Gu and colleagues therefore compared adults with and without diabetes for time trends in mortality from all causes, heart disease, and CHD. Representative cohorts were derived from the First National Health and Nutrition Examination Survey (NHANES I), conducted between 1971 and 1975 (N = 9,639), and from the NHANES I Epidemiologic Follow-Up Survey (NHEFS), conducted between 1982 and 1984 (N = 8,463). The two cohorts were followed up prospectively for mortality for an average of 8–9 years. This slide compares the CHD mortality rates (per 1,000 person-years) between adult men and women with and without diabetes in the two cohorts. For all groups, CHD mortality rates were higher in men than in women and were higher in subjects with diabetes than in those without diabetes. The only statistically significant reduction in CHD mortality in the more recent study occurred in nondiabetic men; diabetic men did not have significantly reduced mortality, and in diabetic women, mortality was slightly increased. References: Rosamond WD, Chambless LE, Folsom AR, et al. Trends in the incidence of myocardial infarction and in mortality due to coronary heart disease: 1987 to N Engl J Med. 1998;13:861–867. Gillum RF. Trends in acute myocardial infarction and coronary heart disease death in the United States. J Am Coll Cardiol. 1994;23:1273–1277. Stamler J. The marked decline in coronary heart disease mortality rates in the United States, 1968–81: summary of findings and possible explanations. Cardiology. 1985;72:11–22. Gu K, Cowie CC, Harris MI. Diabetes and decline in heart disease mortality in US adults. JAMA. 1999;281:1291–1297. 8 7.6 7.4 6.8 6 4.2 4 2.4 1.9 2 } } } } -16.6% (P = 0.46) +10.7% (P = 0.76) -43.8% (P < 0.001) -20.4% (P = 0.12) Gu K et al. JAMA 1999;281:1291–1297

Diferença entre indivíduos com e sem diabetes
Diferenças em Fatores de Risco de Homens e Mulheres com Diabetes The Strong Heart Study HDL-C (mg/dL) LDL (Å) -1 Native Americans -2 Men (n = 1,846) Differences in CVD Risk Factors by Diabetes Status in Men and Women The Strong Heart Study Numerous studies have shown that diabetes increases the risk of cardiovascular disease (CVD) in women to a greater extent than in men. Howard and colleagues compared diabetes-related differences in CVD risk factors in men and women in the Strong Heart Study, a population-based assessment of CVD and its risk factors in Native Americans. The study involved 1,846 men and 2,703 women aged 45–74 years. Significantly greater adverse differences in those with diabetes versus those without diabetes were found in women than in men for high-density lipoprotein cholesterol (HDL-C) level and low-density lipoprotein (LDL) size, as well as for waist-to-hip ratio, apolipoprotein (apo) B, apoA-1, and fibrinogen (not shown in slide). Thus, the women in the Strong Heart Study showed greater diabetes-associated differences in levels of several CVD risk factors compared with men. References: Kannel WB, Wilson PWF. Risk factors that attenuate the female coronary disease advantage. Arch Intern Med. 1995;155:57–61. DeStefano F, Ford ES, Newman J, et al. Risk factors of coronary heart disease mortality among persons with diabetes. Ann Epidemiol. 1993;3:27–34. Sprafka JM, Pankow J, McGovern PG, French LR. Mortality among type 2 diabetic individuals and associated risk factors: the Three City Study. Diabet Med. 1993;10:627–632. Barrett-Connor EL, Cohn BA, Wingard DL, Edelstein SL. Why is diabetes mellitus a stronger risk factor for fatal ischemic heart disease in women than in men? The Rancho Bernardo Study. JAMA. 1991;265:627–631. Howard BV, Cowan LD, Go O, et al. Adverse effects of diabetes on multiple cardiovascular disease risk factors in women: the Strong Heart Study. Diabetes Care.1998;21:1258–1265. -3 Women (n = 2,703) Diferença entre indivíduos com e sem diabetes -4 -3.7 -4.4 -5 -5.3† -6 -7 -7.5* -8 *P = ; †P = Adapted from Howard BV et al. Diabetes Care 1998;21:1258–1265

Estimated hazard ratio
Fatores de Risco Potenciais para DAC em Patientes Brancos com DMNID United Kingdom Prospective Diabetes Study 1 1.48 0.87 1.63 2.29 0.51 1.93 0.5 1.0 1.5 2.0 2.5 LDL-C HDL-C TG 1st 2nd 3rd Tertile Estimated hazard ratio P < 0.001 Potential Risk Factors for CHD in 2,693 White Patients With NIDDM United Kingdom Prospective Diabetes Study The United Kingdom Prospective Diabetes Study evaluated baseline risk factors for coronary heart disease (CHD) in 2,693 white patients with non-insulin-dependent diabetes mellitus (NIDDM). This slide shows the relation of three major risk factors––low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride (TG)––stratified by thirds, to CHD in 280 patients with coronary events (angina or fatal or nonfatal myocardial infarction). As HDL-C increased, the estimated hazard ratio decreased, whereas the opposite was true for LDL-C and TG. Reference: Turner RC, Millns H, Neil HAW, et al. Risk factors for coronary artery disease in non-insulin dependent diabetes mellitus: United Kingdom Prospective Diabetes Study (UKPDS: 23). BMJ. 1998;316:823–828. 280 pts with CHD Turner RC et al. BMJ 1998;316:823–828

Doença Coronariana (n = 280)
Avaliação por Escala dos Fatores de Risco em Patientes Brancos com DMNID United Kingdom Prospective Diabetes Study Doença Coronariana (n = 280) Posição no modelo Variável Valor de P 1º LDL-C <0.0001 2º HDL-C 3º Hemoglobina A1c 4º PA sistólica 5º Tabagismo Stepwise Selection of Risk Factors in 2,693 White Patients With NIDDM United Kingdom Prospective Diabetes Study In the United Kingdom Prospective Diabetes Study (see preceding slide), important risk factors for coronary heart disease (CHD) were selected from the stepwise multivariate Cox model, as shown in this slide. Significant factors were low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), hemoglobin A1C, systolic blood pressure, and smoking (borderline). Factors that were not important were body mass index, waist-to-hip ratio, exercise, triglyceride concentration, and fasting plasma glucose or insulin concentration, and these were not included in the study’s final model. Reference: Turner RC, Millns H, Neil HAW, et al. Risk factors for coronary artery disease in non-insulin dependent diabetes mellitus: United Kingdom Prospective Diabetes Study (UKPDS: 23). BMJ. 1998;316:823–828. Turner RC et al. BMJ 1998;316:823–828

Variáveis antropométricas e fatores de risco cardiovasculares em indivíduos normais e em diabéticos (San Antonio Heart Study) Diabetes Normal (n = 18) (n = 490) Valor deP IMC (kg/m2) TG (mmol/L) HDL-C (mmol/L) PA sistólica (mm Hg) Glicemia (mmol/L) Insulinemia (pmol/L) Baseline Anthropometric Variables and CV Risk Factors in Subjects With Normal Glucose Tolerance (San Antonio Heart Study) Since prediabetic individuals are hyperinsulinemic, and since hyperinsulinemia may be a cardiovascular (CV) risk factor, Haffner and colleagues hypothesized that prediabetic individuals may have an atherogenic pattern of risk factors even before the onset of clinical diabetes. CV risk status was documented in 614 initially nondiabetic Mexican-Americans who subsequently participated in an 8-year follow-up of the San Antonio Heart Study. Individuals who were nondiabetic at baseline but who subsequently developed non-insulin-dependent diabetes mellitus (i.e., confirmed prediabetic subjects) were found to have a higher body mass index as well as significantly higher levels of triglyceride (TG) (P = 0.006), systolic blood pressure (BP) (P = 0.004), fasting glucose (P = 0.032), and fasting insulin (P = 0.006) compared with subjects who remained nondiabetic. The confirmed prediabetic individuals also had significantly lower levels of high-density lipoprotein cholesterol (HDL-C) (P = 0.045). These results indicated that prediabetic subjects have an atherogenic pattern of risk factors that may contribute to the risk of macrovascular disease as much as the duration of clinical diabetes itself. Reference: Haffner SM, Stern MP, Hazuda HP, Mitchell BD, Patterson JK. Cardiovascular risk factors in confirmed prediabetic individuals: does the clock for coronary heart disease start ticking before the onset of clinical diabetes? JAMA.1990;263:2893–2898. Haffner SM et al. JAMA 1990;263:2893–2898

Influência de Múltiplos Fatores de Risco
Influência de Múltiplos Fatores de Risco * na taxa de morte Cardiovascular em Homens Diabéticos e Não diabéticos: MRFIT Screenees Nenhum Apenas 1 Taxa de morte cardiovascular ajustada por idade 10,000 pessoas-ano Todos os três No diabetes Diabetes Apenas 2 Influence of Multiple Risk Factors on CVD Death Rates in Diabetic and Nondiabetic Men: MRFIT Screenees Included among 347,978 screenees for the Multiple Risk Factor Intervention Trial (MRFIT) were 5163 men who reported taking medication for diabetes. In both diabetic and nondiabetic men, the number of risk factors--serum cholesterol >200 mg/dL, cigarette smoking, and systolic blood pressure >120 mm Hg--independently predicted cardiovascular disease (CVD) mortality. What is also striking, however, is that men with diabetes had a higher CVD death rate than nondiabetics with one or even two other cardiovascular risk factors. This finding suggests that, at least in the MRFIT data, type 2 diabetes was more powerful as a single risk factor than hypertension, total cholesterol, or smoking. Reference: Stamler J, Vaccaro O, Neaton JD, Wentworth D. Diabetes, other risk factors, and 12-yr cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial. Diabetes Care 1993;16: *Colesterol >200 mg/dl, tabagismo, PAS >120 mmHg Stamler J, et al. Diabetes Care. 1993;16:

Incidência de IAM e Desfechos Microvasculares pela Medida da Média da Pressão arterial Sistólica : UKPDS IAM Incidência por 1000 Pessoas Ano (%) Incidence Rates of MI and Microvascular Endpoints by Mean Systolic Blood Pressure: UKPDS In the UK Prospective Diabetes Study (UKPDS), systolic blood pressure was equally related to both myocardial infarction and microvascular endpoints. Reference: Adler AI, Stratton IM, Neil HA, Yudkin JS, Matthews DR, Cull CA, Wright AD, Turner RC, Holman RR, on behalf of the UK Prospective Diabetes Study Group. Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): prospective observational study. BMJ 2000;321: Desfechos microvasculares 110 120 130 140 150 160 170 Média da Pressão Arterial Sistólica(mmHg) Adjusted for age, sex, and ethnic group Adler AI, et al. BMJ. 2000;321:

Incidência de IAM e Desfechos Microvasculares pela Medida da Hemoglobina A1c: UKPDS
Incidência por 1000 Pessoas Ano (%) Incidence Rates of MI and Microvascular Endpoints by Mean Hemoglobin A1c: UKPDS In the UKPDS, in contrast with the equal association of systolic blood pressure with both microvascular and macrovascular endpoints, for hemoglobin A1c a stronger relation was found with microvascular complications. Compared with a hemoglobin A1c value of 5.5%, a value of 11% increased risk for microvascular complications tenfold, whereas risk for myocardial infarction was increased only twofold. These differences were highly statistically significant. Reference: Stratton IM, Adler AI, Neil HA, Matthews DR, Manley SE, Cull CA, Hadden D, Turner RC, Holman RR. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 2000;321: Desfechos Microvasculares 5 6 7 8 9 10 11 Média da Hemoglobina A1c Concentração (%) Adjusted for age, sex, and ethnic group Stratton IM, et al. BMJ. 2000;321:

Insulina Plasmática e Triglicerídios Predizem Doença Coronariana: Quebec Cardiovascular Study
6.7 p<0.001 5.4 p=0.002 5.3 4.6 p=0.001 Odds Ratio p=0.005 Trigliceridios Plasma Insulin and Triglycerides Predict Ischemic Heart Disease: Quebec Cardiovascular Study In a nested case-control study within the Quebec Cardiovascular Study, the relationship between fasting insulin, which is a surrogate marker for insulin resistance, and CHD was examined in men who were principally nondiabetic. Subjects were stratified by low (<12 µU/ml), medium (12-15 µU/ml), and high (>15 µU/ml) insulin levels and by low (<150 mg/dL) and high (>150 mg/dL) triglycerides. The study found that high insulin levels predicted CHD both in men with low triglycerides and in men with high triglycerides. However, triglyceride level was not a significant predictor of CHD once one adjusted for insulin level. These results bring up an interesting but difficult area in cardiovascular epidemiology, which is whether triglyceride is a risk factor for CHD. Approximately 20 years ago, Stephen Hulley et al. suggested that triglyceride level was not a risk factor for CHD once adjustment was made for HDL. Although Hulley has been criticized for this view, few analyses that have looked at the possible relation between triglyceride and CHD have adjusted for whether people were diabetic. Because of the relation of triglyceride level to insulin level and possibly glucose level, most of the relation between triglyceride and CHD in observational studies may be due to confounding. To evaluate fully the effects of lowering triglyceride level on CHD, one has to look at clinical trial data as opposed to observational data. Among interventional studies, confounding may be less important in trials of behavioral interventions to lower triglyceride, because weight loss and increased physical activity not only lower triglyceride level but also improve insulin sensitivity and lower blood pressure. In contrast, if triglyceride is lowered by pharmacological means such as with a fibrate or a high-dose statin, there will be little effect on blood pressure or insulin sensitivity. References: Despres JP, Lamarche B, Mauriege P, Cantin B, Dagenais GR, Moorjani S, Lupien PJ. Hyperinsulinemia as an independent risk factor for ischemic heart disease. N Engl J Med 1996;334: Hulley SB, Rosenman RH, Bawol RD, Brand RJ. Epidemiology as a guide to clinical decisions. The association between triglyceride and coronary heart disease. N Engl J Med 1980;302: 1.5 >150 mg/dl 1.0 <150 mg/dl <12 12-15 >15 F-Insulina (U/ml) Despres JP, et al. N Engl J Med. 1996;334:

Incidencia Durante Follow-up (%)
Incidência de IAM fatal e não fatal em um Follow-up de 7 anos em relação a História Prévia de IAM em Não diabéticos vs. Diabéticos : East-West Study 45.0 Não diabeticos com IAM prévio Não diabeticos sem IAM prévio Diabeticos com IAM prévio Diabetics sem IAM prévio p<0.001 Incidencia Durante Follow-up (%) 20.2 18.8 P<0.001 Incidence of Fatal or Nonfatal MI During a 7-Year Follow-up in Relation to History of MI in Nondiabetic vs. Diabetic Subjects: East-West Study In the East-West Study, diabetics with prior myocardial infarction had a higher incidence of myocardial infarction than diabetics without prior myocardial infarction, but more importantly, diabetics without prior myocardial infarction had a 20.2% incidence of myocardial infarction at 7-year follow-up, compared with an 18.8% incidence in nondiabetics with prior myocardial infarction. These results were important in establishing diabetes as a CHD risk equivalent. Although this study was criticized because it was conducted in a relatively high-risk population for CHD, namely Finland in the early 1980s, a subsequently published analysis of the Organization to Assess Strategies for Ischemic Syndromes (OASIS) Registry, which included prospective data from 6 countries (Australia, Brazil, Canada, Hungary, Poland, and the United States), also found that diabetic patients without prior cardiovascular disease had the same event rates as nondiabetic patients with prior cardiovascular disease. References: Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med 1998;339: Malmberg K, Yusuf S, Gerstein HC, Brown J, Zhao F, Hunt D, Piegas L, Calvin J, Keltai M, Budaj A. Impact of diabetes on long-term prognosis in patients with unstable angina and non-Q-wave myocardial infarction: results of the OASIS (Organization to Assess Strategies for Ischemic Syndromes) Registry. Circulation 2000;102: 3.5 (n=69) (n=1304) (n=169) (n=890) Eventos por 100 pesoas-ano: 3.0 0.5 7.8 3.2 Haffner SM, et al. N Engl J Med. 1998;339:

Pacientes Diabéticos vs. Não diabéticos in 4S
Placebo Melhor Simvastatina Melhor P= P=0.087 Mortalidade Total P< P=0.242 Mortalidade CV P< P=0.002 Ev CV Maior Diabetic vs. Nondiabetic Patients in 4S In 4S, 202 subjects with diagnosed diabetes, based on patient records before baseline examination, were compared with nondiabetic subjects. Relative risk for major coronary events was significantly reduced by 55% in diabetic subjects and by 32% in nondiabetic subjects. Risk for any atherosclerotic event was also significantly reduced in diabetics. There were also tendencies toward improvements in CHD mortality and total mortality. Reference: Pyörälä K, Pedersen TR, Kjekshus J, Faergeman O, Olsson AG, Thorgeirsson G, Scandinavian Simvastatin Survival Study (4S) Group. Cholesterol lowering with simvastatin improves prognosis of diabetic patients with coronary heart disease: a subgroup analysis of the Scandinavian Simvastatin Survival Study (4S). Diabetes Care 1997;20: P= P=0.071 Ev Cerebrovascular Qualquer ev vascular P< P=0.018 0.2 0.4 0.6 0.8 1.0 1.2 1.4 Risco Relativo com IC 95% Não diabético Diabético Reduzida Aumentada Adapted from Pyörälä et al. Diabetes Care 1997;20:

CARE: Eventos Coronarianos Maiores em Subgrupos Diabéticos
Sem Diabetes pela História Diabetes pela História 45 35 30 25 20 15 10 5 45 35 30 25 20 15 10 5 Relative risk = P<0.001 Relative risk = P=0.05 Placebo Placebo Percentual com Evento CARE: Major Coronary Events in Diabetic Subgroups In a subgroup analysis of CARE, which studied patients with prior CHD and relatively low LDL cholesterol levels, patients with a history of diabetes had a 25% reduction in CHD risk with pravastatin, similar to the 23% reduction in the nondiabetics. As in 4S, statin therapy was associated with similar reductions in CHD in both diabetics and nondiabetics, although the percent of CHD reduction was somewhat less in CARE than in 4S. Reference: Goldberg RB, Mellies MJ, Sacks FM, Moye LA, Howard BV, Howard WJ, Davis BR, Cole TG, Pfeffer MA, Braunwald E. Cardiovascular events and their reduction with pravastatin in diabetic and glucose-intolerant myocardial infarction survivors with average cholesterol levels: subgroup analyses in the Cholesterol and Recurrent Events (CARE) trial. Circulation 1998;98:2513‑2519. Percentual com Evento Pravastatina Pravastatina 1 2 3 4 6 5 1 2 3 4 6 5 Follow-up Time (anos) Follow-up Time (anos) Adapted from Goldberg RB et al. Circulation 1998;98:

HOT Trial: Eventos Cardiovasculares em Diabéticos e Não diabéticos—Efeito da meta Diastólica em 4 anos 48% Redução Risco 24.4 18.6 Eventos/1000 pac-ano 11.9 9.9 10.0 9.3 HOT Trial: Cardiovascular Events in Diabetics and Nondiabetics—Effect of Diastolic Target at 4 Years In patients without diabetes mellitus in the HOT Trial, there was no difference in the cardiovascular event rate at 4 years regardless of the diastolic blood pressure achieved, whereas in patients with diabetes mellitus, the lower the diastolic blood pressure the lower the risk of cardiovascular events. These data suggest that as blood pressure is lowered more aggressively in patient with diabetes, the additional medications required, such as ACE inhibitors, may provide a benefit in risk reduction beyond blood pressure lowering itself. This effect may not be apparent in patients without diabetes. Reference: Hansson L, Zanchetti A, Carruthers SG, Dahlof B, Elmfeldt D, Julius S, Menard J, Rahn KH, Wedel H, Westerling S, for the HOT Study Group. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. Lancet 1998;351: <90 <85 <80 <90 <85 <80 Diabeticos sn=1,501; p=0.016 Não diabetic n=18,790; p=NS Hansson L, et al. Lancet. 1998;351:

Heart Outcomes Prevention Evaluation (HOPE) Study: Efeito do Ramipril em Eventos Cardiovasculares (IAM, AVE, ou morte CV) ~ 4.5 anos 24% Redução Risco 21% Redução Risco 19.8 % dos Pacientes 16.4 15.0 13.0 Heart Outcomes Prevention Evaluation (HOPE) Study: Effect of Ramipril on Cardiovascular Events (Myocardial Infarction, Stroke, or CVD Death) ~4.5 Yrs In the Heart Outcomes Prevention Evaluation (HOPE) Study, diabetic patients randomized to ramipril had a 24% risk reduction compared with diabetic patients randomized to placebo. A similar risk reduction was seen in the nondiabetic patients randomized to active therapy. Patients with diabetes in the HOPE Trial required only one additional risk factor for inclusion. These data suggest that ramipril, a tissue-specific ACE inhibitor, may provide cardiovascular protection in diabetic patients with associated risk factors even in the absence of a prior history of cardiovascular disease or a diagnosis of hypertension. Reference: Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med 2000;342: Placebo Ramipril Placebo Ramipril Diabetic Não diabeticos N=3,578, P 0.001 N=5,719, P 0.001 Hope Study Investigators. N Engl J Med. 2000;342:

Prevalência de DAC Assintomática na Diabetes Mellitus
TE Positivo Coronariografia Positiva n = n = n = 80 n = n = 149 n = 925 n = n = 43 36% % % 31% % 12.1% 65% % 58% 55% 9% % % 12.1% % 6.4% — — 35% 43% Koistinen MJ. BMJ 1990;301:92-95. Tipo Tipo Controles Naka M et al. Am Heart J 1992;123:46-53. Type 2 Controles MiSAD Group. Am J Cardiol 1997;79: Tipo 2 Rutter MK et al. Am J Cardiol 1999;83:27-31. Tipo 2 c microalb Tipo 2 s microalb Le A et al. Am J Kidney Dis 1994;24:65-71. Tipo 1 Transplante renal Renal Holley JL et al. Am J Med 1991;90: Tipo 1 & 2 Transplante Renal (thal201) Prevalence of Asymptomatic CAD in Diabetes Mellitus Patients with diabetes mellitus have a defective ability to experience angina. This is most prevalent in diabetic patients with autonomic neuropathy. Patients with diabetes mellitus also have a 2–4 times higher risk for death from cardiovascular disease compared with patients without diabetes. Some studies have evaluated the outcome of screening for coronary artery disease in patients with diabetes mellitus. The studies depicted in this slide show that the rate of detection of coronary artery disease varies with the extent of diabetes-related complications. The presence of either diabetic nephropathy, autonomic neuropathy, or other vascular disease denotes a diabetic group with a particularly high prevalence of asymptomatic coronary artery disease. References: Koistinen MJ. Prevalence of asymptomatic myocardial ischaemia in diabetic subjects. BMJ 1990;301:92-95. Naka M, Hiramatsu K, Aizawa T, Momose A, Yoshizawa K, Shigematsu S, Ishihara F, Niwa A, Yamada T. Silent myocardial ischemia in patients with non-insulin-dependent diabetes mellitus as judged by treadmill exercise testing and coronary angiography. Am Heart J 1992;123:46-53. Milan Study on Atherosclerosis and Diabetes (MiSAD) Group. Prevalence of unrecognized silent myocardial ischemia and its association with atherosclerotic risk factors in noninsulin-dependent diabetes mellitus. Am J Cardiol 1997;79: Rutter MK, McComb JM, Brady S, Marshall SM. Silent myocardial ischemia and microalbuminuria in asymptomatic subjects with non-insulin-dependent diabetes mellitus. Am J Cardiol 1999;83:27-31. Le A, Wilson R, Douek K, Pulliam L, Tolzman D, Norman D, Barry J, Bennett W. Prospective risk stratification in renal transplant candidates for cardiac death. Am J Kidney Dis 1994;24:65-71. Holley JL, Fenton RA, Arthur RS. Thallium stress testing does not predict cardiovascular risk in diabetic patients with end-stage renal disease undergoing cadaveric renal transplantation. Am J Med 1991;90:

Indicações para Avaliação Cardíaca em Pacientes Diabéticos
Simtomas Tipicos ou atipicos ECG de repouso sugestivo de isquemia ou infarto Doença carotídea ou periférica Estilo de vida sedentário ou planejamento de iniciar programa de exercício Dois ou maios fatores de risco  Colesterol Total ≥240 mg/dL, LDL colesterol ≥160 mg/dL, or HDL cholesterol <35 mg/dL  PA >140/90 mmHg  Tabagismo  História familiar de DAC em idade baixa  Presença de microalbuminúrioa Indications for Cardiac Testing in Diabetic Patients Because patients with diabetes have defective angina perception and increased risk for coronary artery disease, testing for coronary artery disease may be warranted in the asymptomatic diabetic patient. This slide shows those factors that would encourage screening in these patients. At present, exercise testing is recommended, particularly if the patient has evidence of vascular disease by history or physical examination, or has additional cardiovascular risk factors including proteinuria.

Cardiopatia Hipertensiva Cardiomiopatia Diabética
Factores Limitantes na Acurácia dos Testes Não invasivos de "Stress" para DAC Cardiopatia Hipertensiva Cardiomiopatia Diabética Cardiomiopatia Autonômica Insuficiência Renal Disfunção Microvascular Factors Limiting Accuracy of Noninvasive "Stress" Tests for CAD Patients with diabetes have several factors that limit the sensitivity and specificity of noninvasive testing for coronary artery disease. More than 70% of type 2 diabetic patients have hypertension, which can produce resting ST- and T-wave changes and decrease the specificity of ST segment depression on the exercise tolerance test for the diagnosis of coronary disease. Furthermore, patients with diabetes may have subclinical cardiomyopathy that may also impair left ventricular ejection fraction response to an exercise, exercise echocardiography, or dobutamine echocardiography stress test. Autonomic neuropathy in the diabetic patient may impair appropriate heart rate and blood pressure response to exercise limiting functional capacity. Renal insufficiency may reduce the sensitivity of persantine stress perfusion imaging. The presence of microvascular dysfunction in patients with diabetes may also limit perfusion and possibly produce exercise-induced wall motion abnormalities.

Benefícios da Detecção Precoce da DAC
Implementar uma estratégia agressiva de prevenção cardiovascular Iniciar medicações anti-isquemicas Identificar pacientes que poderiam beneficiar-se da revascularização Educar pacientes a reconhecer os sintomas de uma síndrome coronariana Benefits of Early Detection of CAD Detecting coronary artery disease in the diabetic patient may enable the initiation of anti-ischemic medications such as beta-blockers. Patients could be advised to adhere to aggressive secondary-prevention techniques. Patients with asymptomatic but severe coronary artery disease may benefit from early coronary revascularization. Finally, when patients are found to have coronary artery disease, they are more likely to evaluate symptoms suggestive of coronary disease that they might otherwise consider atypical for symptoms of myocardial ischemia.

Efeito da Aspirina na Mortalidade de Pacientes com DM 2 e DAC: Bezafibrate Infarction Prevention Study OR=0.7 ( ) Sem diabetes Sobrevida (%) OR=0.8 ( ) Effect of Aspirin on Mortality in Type 2 Patients with CHD: Bezafibrate Infarction Prevention Study Patients with diabetes mellitus have increased platelet aggregation, which may account for some of their increased risk for myocardial infarction and stroke. Aspirin in the BIP Study improved survival in both patients with and patients without diabetes. This study was a secondary-prevention study using a fibrate to treat hypercholesterolemia. Other trials have shown that aspirin provides both primary and secondary prevention against cardiovascular events in patients with diabetes. Reference: Harpaz D, Gottlieb S, Graff E, Boyko V, Kishon Y, Behar S, for the Israeli Bezafibrate Infarction Prevention Study Group. Effects of aspirin treatment on survival in non-insulin-dependent diabetic patients with coronary artery disease. Am J Med 1998;105: DM 2 Aspirina Sem aspirina 1 2 3 4 5 6 Tempo (anos) Harpaz D, et al. Am J Med. 1998;105:

Agentes Antiplaquetários Reduzem Eventos CV em Pacientes com Diabetes: Antiplatelet Trialists’ Collaboration P<0.002 Terapia Antiplaquetária Controle P< Antiplatelet Agents Reduce CVD Events in Patients with Diabetes: Antiplatelet Trialists' Collaboration In the Antiplatelet Trialists' Collaboration analysis, which included 174 studies with approximately 100,000 patients, patients with diabetes had a significant reduction in cardiovascular disease, with a reduction in relative risk similar to that of patients without diabetes. Reference: Antiplatelet Trialists' Collaboration. Collaborative overview of randomised trials of antiplatelet therapy—I: Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. BMJ 1994;308: Eventos CV (%) Diabetes Sem Diabetes Antiplatelet Trialists’ Collaboration. BMJ. 1994;308:

Mortalidade em 5 anos no Estuda BARI – Bypass Angioplasty Revascularization Investigation (BARI-1)
DM-PTCA DM-CABG Sem DM-CABG Sem DM-PTCA Mortalidade 0.25 Overall 5-Year Mortality in the Bypass Angioplasty Revascularization Investigation (BARI-1) In the Bypass Angioplasty Revascularization Investigation (BARI) Trial, patients with angina and multivessel coronary artery disease demonstrated on coronary angiography were randomized either to percutaneous transluminal coronary angioplasty (PTCA) or to coronary artery bypass graft (CABG) surgery. In patients without diabetes, there was no difference in 5-year cardiac or overall mortality in the randomized treatment groups. In the group with diabetes mellitus, however, the group randomized to multivessel coronary bypass graft surgery had a much better survival than the diabetic group randomized to multivessel balloon angioplasty. The benefit of bypass surgery in diabetic patients occurred solely in those patients who received an arterial conduit as part of their coronary bypass operation. Reference: Detre KM, Lombardero MS, Brooks MM, Hardison RM, Holubkov R, Sopko G, Frye RL, Chaitman BR, for the Bypass Angioplasty Revascularization Investigation Investigators. The effect of previous coronary-artery bypass surgery on the prognosis of patients with diabetes who have acute myocardial infarction. N Engl J Med 2000;342: 0.18 0.08 0.07 1 2 3 4 5 Follow-up (anos) Detre KM, et al. N Engl J Med. 2000;342:

OASIS Estudo: Mortalidade Total
Diabetes/CVD (n = 1148) RR=2.88 (2.37–3.49) Diabetes/Sem CVD (n = 569) Sem Diabetes/CVD (n = 3503) Sem Diabetes/Sem CVD (n = 2796) RR=1.99 (1.52–2.60) Frequencia do Evento OASIS study: total mortality The OASIS study also supports the concept of diabetes as a CHD risk equivalent. This study is more generalizable than the Finnish East-West study since it was based in 6 different countries and has a larger population. Reference: Malmberg K, Yusuf S, Gerstein HC, Brown J, Zhao F, Hunt D, Piegas L, Calvin J, Keltai M, Budaj A. Impact of diabetes on long-term prognosis in patients with unstable angina and non-Q-wave myocardial infarction: results of the OASIS (Organization to Assess Strategies for Ischemic Syndromes) Registry. Circulation 2000;102: RR=1.71 (1.44–2.04) RR=1.00 3 6 9 12 15 18 21 24 Meses Malmberg K et al. Circulation 2000;102: ©2000 Lippincott Williams & Wilkins.

Initiation Level for TLC Consideration Level for Drug Therapy
Metas ATP III LDL-C Categoria de Risco LDL-C (mg/dL) Meta Initiation Level for TLC Consideration Level for Drug Therapy High risk: CHD or CHD risk equivalents (10-yr risk >20%) <100 (optional: <70) 100 100 (<100: consider drug options) Moderately high risk: 2+ risk factors (10-yr risk 10–20%) <130 (optional: <100) 130 130 (100–129: consider drug options) Moderate risk: 2+ risk factors (10-yr risk <10%) <130 160 Lower risk: 0–1 risk factor <160 190 (160–189: LDL-C–lowering drug optional) Updated ATP III LDL-C Goals and Cutpoints for Therapy The National Cholesterol Education Program Adult Treatment Panel III (ATP III) defines high-risk patients as those who have CHD or atherosclerotic disease of the blood vessels to the brain or extremities, or diabetes, or multiple (2 or more) risk factors (e.g., smoking, hypertension) that give them a >20% chance of having a heart attack within 10 years. Very high risk patients are those who have cardiovascular disease together with (1) multiple risk factors (especially diabetes), or severe and poorly controlled risk factors (e.g., continued smoking), (2) metabolic syndrome (a constellation of risk factors associated with obesity including high triglycerides and low high-density lipoprotein cholesterol [HDL-C]) and/or (3) acute coronary syndromes such as heart attack. For high-risk patients, the overall goal is to achieve a low-density lipoprotein cholesterol (LDL-C) level of <100 mg/dL. But for patients at very high risk, a group that is considered a "subset" of the high-risk category, a therapeutic option is to decrease LDL-C levels to <70 mg/dL. For very high risk patients whose LDL-C levels are already <100 mg/dL, there is also an option to use drug therapy to reach the <70-mg/dL treatment goal. For moderately high risk patients, the goal is to achieve an LDL-C level <130 mg/dL, but it is a therapeutic option to set a lower LDL-C goal of <100 mg/dL and to use drug therapy for LDL-C levels of 100–129 mg/dL to achieve this lower goal. For high-risk or moderately high risk patients, the report advises that LDL-C–lowering drug therapy be sufficient to achieve at least a 30–40% reduction in LDL-C levels. This can be accomplished by taking statins or by combining lower doses of statins with other drugs (bile acid resins, nicotinic acid, or ezetimibe) or with food products containing plant stanols/sterols. For moderately high risk patients with LDL-C levels of 100–129 mg/dL at baseline or on lifestyle therapy, LDL-C–lowering therapy to reach a goal of <100 mg/dL is recommended, and lipid-altering drug therapy to achieve this goal is a therapeutic option. By definition, almost all people with 0–1 risk factor have a 10-year risk <10%. Drug therapy for primary prevention in this patient population is recommended only for those with higher LDL-C levels. Major CHD risk factors include cigarette smoking, blood pressure 140/90 mm Hg or on antihypertensive medication, HDL-C <40 mg/dL (1.0 mmol/L), family history of premature CHD (CHD in male first-degree relative aged <55 years; CHD in female first-degree relative aged <65 years), and age (men 45 years; women 55 years). HDL-C  60 mg/dL (1.6 mmol/L) counts as a "negative" risk factor; its presence removes 1 risk factor from the total count. Framingham risk score may also be used to determine 10-year CHD risk. References: National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 2002;106: Grundy SM, Cleeman JI, Bairey Merz CN, et al., for the Coordinating Committee of the National Cholesterol Education Program. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 2004;110: Bays H, Shepherd J. Diabetes, metabolic syndrome and dyslipidemia. In: Management Strategies in Diabetes. Hackensack, NJ: Cambridge Medical Publications, 2004:1-28. Reprinted from Grundy SM et al. Circulation 2004;110: , with permission from Lippincott Williams & Wilkins.

DREAM: Primary Outcome by Subgroups–Rosiglitazone
Overall P (Heterogeneity) Males Female Age <50 50-59 60+ North America South America Europe India Australia IFG only IGT only IFG & IGT Favors Rosiglitazone Favors Placebo 0.6 0.09 DREAM: Primary outcome by subgroups-rosiglitazone This slide shows primary outcome by subgroups. Note that rosiglitazone was equally effective in males and females in younger and older subjects by region and whether people started with impaired fasting glucose, impaired glucose tolerance or both. Also, note that subjects with both impaired fasting glucose and impaired glucose tolerance had approximately twice the rate of conversion to new diabetes compared to subjects with isolated impaired fasting glucose or impaired glucose tolerance. DREAM = Diabetes REduction Approaches with ramipril and rosiglitazone Medications Reference: The DREAM Trial Investigators. Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial. Lancet 2006;368: 0.09 0.14 0.0 0.2 0.4 0.6 0.8 1.0 1.2 The DREAM Trial Investigators. Lancet 2006;368:

DREAM: Peso e IMC–Rosiglitazone
Peso (Kg) IMC (Kg/m2) Rosigitazone Rosigitazone DREAM: weight and BMI-rosiglitazone Subjects in the DREAM study who were on rosiglitazone continued to gain more weight throughout the study than subjects in the placebo group. DREAM = Diabetes REduction Approaches with ramipril and rosiglitazone Medications Reference: The DREAM Trial Investigators. Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial. Lancet 2006;368: Placebo Placebo P<0.0001 P<0.0001 Year 1 2 3 4 5 1 2 3 4 5 Year Peso (kg) IMC (kg/m2) 0.67 (2.77) 0.25 (1.01) -0.09 (2.41) -0.01 (0.84) Change/yr (Slope) Rosiglitazone Placebo The DREAM Trial Investigators. Lancet 2006;368:

DREAM: Prognóstico Cardiovascular Rosiglitazone
Composite IAM AVE Morte CV IC Angina Revascularização HR 1.37 ( ); P=0.08 DREAM: Cardiovascular outcomes-rosiglitazone Although the event rate was very low, subjects in the rosiglitazone group had a significant increase in congestive heart failure. They also had increases in other cardiovascular endpoints, although none of these were statistically significant. DREAM = Diabetes REduction Approaches with ramipril and rosiglitazone Medications Reference: The DREAM Trial Investigators. Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial. Lancet 2006;368: 14 (0.5%) vs. 2 (0.1%); P=0.01 0.5 1.0 2.0 4.0 10.0 20.0 90.0 LOG HR (95% CI) The DREAM Trial Investigators. Lancet 2006;368:

Controle Pressorico - Recomendacões
Fator de risco Normal Limítrofe Estágio 1 Estágio 2 Estágio 3 Sem risco adicional Risco baixo Risco médio Risco alto Sem FR Risco baixo Risco médio Risco médio Risco muito alto 1 a 2 FR Blood pressure control: recommendations Component: blood pressure control Goal: 140/90 mm Hg or 130/80 mm Hg if patient has diabetes or chronic kidney disease Recommendations: For all patients: Initiate or maintain lifestyle modification, including: weight control, increased physical activity, alcohol moderation, sodium reduction, and a diet that emphasizes an increased consumption of fresh fruits, vegetables, and low-fat dairy products. I (B) For patients with blood pressure >140/90 mm Hg (or >130/80 mm Hg for individuals with chronic kidney disease or diabetes): As tolerated, add blood pressure medication, treating initially with beta-blockers and/or ACE inhibitors with the addition of other drugs such as thiazides as needed to achieve goal blood pressure. I (A) To view indications for individual drug classes in specific vascular diseases, see the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7). I=Procedure or treatment SHOULD be performed or administered (A)=Multiple randomized controlled trials (B)=Single trial, non-randomized studies Reference: Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, Jones DW, Materson BJ, Oparil S, Wright JT Jr, Roccella EJ; Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. National Heart, Lung, and Blood Institute; National High Blood Pressure Education Program Coordinating Committee. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 2003;42: Smith SC Jr, Allen J, Blair SN, Bonow RO, Brass LM, Fonarow GC, Grundy SM, Hiratzka L, Jones D, Krumholz HM, Mosca L, Pasternak RC, Pearson T, Pfeffer MA, Taubert KA; AHA/ACC; National Heart, Lung, and Blood Institute. AHA/ACC guidelines for secondary prevention for patients with coronary and other atherosclerotic vascular disease: 2006 update: endorsed by the National Heart, Lung, and Blood Institute. Circulation 2006;113: 3+ FR ou lesão de órgão-alvo ou DM Risco médio Risco alto Risco alto Risco alto Risco muito alto Risco alto Risco muito alto Risco muito alto Risco muito alto Risco muito alto DCV

Controle Pressorico - Recomendacões
Categorias Meta (mínimo) Hipertensos estágios 1 e 2 com RCV baixo e médio Hipertensos nefropatas com proteinúria >1,0g/l <140/90 mmHg <130/85 mmHg <130/80 mmHg <120/75 mmHg Hipertensos e limítrofes com RCV alto Hipertensos e limítrofes com RCV muito alto Blood pressure control: recommendations Component: blood pressure control Goal: 140/90 mm Hg or 130/80 mm Hg if patient has diabetes or chronic kidney disease Recommendations: For all patients: Initiate or maintain lifestyle modification, including: weight control, increased physical activity, alcohol moderation, sodium reduction, and a diet that emphasizes an increased consumption of fresh fruits, vegetables, and low-fat dairy products. I (B) For patients with blood pressure >140/90 mm Hg (or >130/80 mm Hg for individuals with chronic kidney disease or diabetes): As tolerated, add blood pressure medication, treating initially with beta-blockers and/or ACE inhibitors with the addition of other drugs such as thiazides as needed to achieve goal blood pressure. I (A) To view indications for individual drug classes in specific vascular diseases, see the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7). I=Procedure or treatment SHOULD be performed or administered (A)=Multiple randomized controlled trials (B)=Single trial, non-randomized studies Reference: Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, Jones DW, Materson BJ, Oparil S, Wright JT Jr, Roccella EJ; Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. National Heart, Lung, and Blood Institute; National High Blood Pressure Education Program Coordinating Committee. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 2003;42: Smith SC Jr, Allen J, Blair SN, Bonow RO, Brass LM, Fonarow GC, Grundy SM, Hiratzka L, Jones D, Krumholz HM, Mosca L, Pasternak RC, Pearson T, Pfeffer MA, Taubert KA; AHA/ACC; National Heart, Lung, and Blood Institute. AHA/ACC guidelines for secondary prevention for patients with coronary and other atherosclerotic vascular disease: 2006 update: endorsed by the National Heart, Lung, and Blood Institute. Circulation 2006;113:

Controle intensivo do LDL colesterol Recommended LDL-C treatment goals
ATP III Update 20041 <100 mg/dL: Patients with CHD or CHD risk equivalents (10 year risk >20%)1 <70 mg/dL: Therapeutic option for very high risk patients1 AHA/ACC guidelines for patients with CHD*,2 <100 mg/dL: Goal for all patients with CHD†,2 <70 mg/dL: A reasonable goal for all patients with CHD2 2006 Update <100 mg/dL Intensive LDL-C goals for high risk patients Key points: Clinical trial evidence led to proposed modifications of the ATP III low-density lipoprotein (LDL-C) goals and cut points for therapeutic lifestyle changes (TLC) and drug therapy. AHA/ACC recently updated guidelines for secondary prevention for patients with coronary heart disease (CHD) and other atherosclerotic vascular disease. These guidelines include recommendations regarding lipid management. Additional Background Information: Factors that place patients in the very high-risk category include the presence of established cardiovascular disease plus the following: Multiple major risk factors, especially diabetes Severe and poorly controlled risk factors, especially continued cigarette smoking Multiple risk factors of the metabolic syndrome, especially high triglycerides (TG) ≥200 mg/dL plus non–high-density lipoprotein (HDL-C) ≥130 mg/dL with HDL-C <40 mg/dL and 4) Acute coronary syndromes From Grundy SM et al. Circulation 2004;110:227–239: For high-risk patients, the recommended LDL-C treatment goal remains <100 mg/dL. However, an optional target of <70 mg/dL is a reasonable clinical strategy for persons considered to be at very high risk. Any person at high risk who has lifestyle-related risk factors is a candidate for TLC to modify these risk factors, regardless of LDL-C level. As before, whenever the baseline concentration is ≥130 mg/dL, simultaneous initiation of an LDL-C-lowering drug and dietary therapy is recommended. If LDL-C is 100 to 129 mg/dL, the same now holds. Smith SC Jr et al. Circulation 2006; 113:2363–2372: Patients at high risk include those with established atherosclerotic vascular disease. A recent update to the AHA/ACC guidelines for secondary prevention further supports the intensive reduction of LDL-C in patients with coronary heart disease and other atherosclerotic vascular disease. The recommended LDL-C treatment goal in these patients is <100 mg/dL, but a target of <70 mg/dL is now considered a reasonable strategy. Any person at high risk who has lifestyle-related risk factors is a candidate for TLC to modify these risk factors, regardless of LDL-C level. Whenever the baseline LDL-C concentration is ≥100 mg/dL, initiation of an LDL-C–lowering drug and dietary therapy is recommended. If baseline LDL-C is 70 to 100 mg/dL, it is now reasonable to lower it to <70 mg/dL. ATP III=National Cholesterol Education Program Adult Treatment Panel III AHA=American Heart Association ACC= American College of Cardiology Non-HDL-C=non-high-density lipoprotein cholesterol HDL-C=high-density lipoprotein cholesterol LDL-C=low-density lipoprotein cholesterol References: Grundy SM, Cleeman JI, Merz CN, Brewer HB Jr, Clark LT, Hunninghake DB, Pasternak RC, Smith SC Jr, Stone NJ; National Heart, Lung, and Blood Institute; American College of Cardiology Foundation; American Heart Association. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 2004;110: Smith SC Jr, Allen J, Blair SN, Bonow RO, Brass LM, Fonarow GC, Grundy SM, Hiratzka L, Jones D, Krumholz HM, Mosca L, Pasternak RC, Pearson T, Pfeffer MA, Taubert KA; AHA/ACC; National Heart, Lung, and Blood Institute. AHA/ACC guidelines for secondary prevention for patients with coronary and other atherosclerotic vascular disease: 2006 update: endorsed by the National Heart, Lung, and Blood Institute. Circulation 2006;113: <70 mg/dL If it is not possible to attain LDL-C <70 mg/dL because of a high baseline LDL-C, it generally is possible to achieve LDL-C reductions of >50% with more intensive LDL-C–lowering therapy, including drug combinations. * And other forms of atherosclerotic disease.2 † Factors that place a patient at very high risk: established cardiovascular disease plus: multiple major risk factors (especially diabetes); severe and poorly controlled risk factors (e.g., cigarette smoking); metabolic syndrome (triglycerides ≥200 mg/dL + non–HDL-C ≥130 mg/dL with HDL-C <40 mg/dL); and acute coronary syndromes.1 1. Grundy SM et al. Circulation 2004;110:227–239. 2. Smith SC Jr et al. Circulation 2006; 113:2363–2372.

20% Reducao de risco absoluto
Intervencão em Multiplos Fatores de Risco em pacientes com DM 2: STENO-2 N=160; follow-up = 7.8 anos Terapia convencional 20% Reducao de risco absoluto Desfecho composto* (%) Intensive multiple risk factor management in patients with type 2 diabetes: STENO-2 The STENO-2 study randomized 160 patients (mean age of 55 years) with type 2 diabetes and microalbuminuria to targeted intensive multifactorial intervention or conventional treatment of cardiovascular risk factors for 8 years. The targeted intervention involved pharmacologic therapy and behavior modification targeting dyslipidemia, hyperglycemia, hypertension, microalbuminuria, and secondary prevention of cardiovascular disease with aspirin. The primary end point was a composite of nonfatal myocardial infarction, cardiovascular death, revascularization, nonfatal stroke, and amputation. The hazard ratio for the primary end point in the intensive group was 0.47 (95% CI, 0.22 to 0.74; P=0.01). Reference: Gaede P, Vedel P, Larsen N, Jensen GV, Parving HH, Pedersen O. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med 2003;348: Aggressive treatment of†: Microalbuminuria com ACEIs, ARBs, ou combinacao Hipertensão Hiperglicemia Dislipidemia Prevencao Secondaria Terapia intensiva† 12 24 36 48 72 96 60 84 Meses de follow up Adapted from Gaede P et al. N Eng J Med 2003;348:383–393.

Qual o melhor teste diagnostico para DAC em pacientes com DM ?
DAC é mais prevalente e grave. Ocorre em idade mais Jovem. Diabetes é o equivalente de DAC. Maior frequência de isquemia silenciosa. Intensive multiple risk factor management in patients with type 2 diabetes: STENO-2 The STENO-2 study randomized 160 patients (mean age of 55 years) with type 2 diabetes and microalbuminuria to targeted intensive multifactorial intervention or conventional treatment of cardiovascular risk factors for 8 years. The targeted intervention involved pharmacologic therapy and behavior modification targeting dyslipidemia, hyperglycemia, hypertension, microalbuminuria, and secondary prevention of cardiovascular disease with aspirin. The primary end point was a composite of nonfatal myocardial infarction, cardiovascular death, revascularization, nonfatal stroke, and amputation. The hazard ratio for the primary end point in the intensive group was 0.47 (95% CI, 0.22 to 0.74; P=0.01). Reference: Gaede P, Vedel P, Larsen N, Jensen GV, Parving HH, Pedersen O. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med 2003;348:

Sensitivity and Specificity of Non-invasive Tests for the Diagnosis of CAD*
Diagnostic Test Sensitivity % (range) Specificity% (range) # Studies # Patients TMT 68 77 132 24,027 Planar MPI 79 (70-94) 73 (43-97) 6 510 SPECT 88 (73-98) (53-96) 8 628 Stress echo 76 (40-100) (80-95) 10 1174 * NEJM Vol. 344, No. 24 June 14, 2004

Teste Ergometrico Reproduz sintomas, eletrocardiograma e variáveis fisiológicas Intensive multiple risk factor management in patients with type 2 diabetes: STENO-2 The STENO-2 study randomized 160 patients (mean age of 55 years) with type 2 diabetes and microalbuminuria to targeted intensive multifactorial intervention or conventional treatment of cardiovascular risk factors for 8 years. The targeted intervention involved pharmacologic therapy and behavior modification targeting dyslipidemia, hyperglycemia, hypertension, microalbuminuria, and secondary prevention of cardiovascular disease with aspirin. The primary end point was a composite of nonfatal myocardial infarction, cardiovascular death, revascularization, nonfatal stroke, and amputation. The hazard ratio for the primary end point in the intensive group was 0.47 (95% CI, 0.22 to 0.74; P=0.01). Reference: Gaede P, Vedel P, Larsen N, Jensen GV, Parving HH, Pedersen O. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med 2003;348:

Ecocardiograma de estrese farmacologico com dobutamina
Protocolo próprio para analisar isquemia miocárdica Limitação do examinador Análise da janela ecocardiográfica Atenção para a frequencia cardíaca Sensibilidade 84% - VPN 50% Intensive multiple risk factor management in patients with type 2 diabetes: STENO-2 The STENO-2 study randomized 160 patients (mean age of 55 years) with type 2 diabetes and microalbuminuria to targeted intensive multifactorial intervention or conventional treatment of cardiovascular risk factors for 8 years. The targeted intervention involved pharmacologic therapy and behavior modification targeting dyslipidemia, hyperglycemia, hypertension, microalbuminuria, and secondary prevention of cardiovascular disease with aspirin. The primary end point was a composite of nonfatal myocardial infarction, cardiovascular death, revascularization, nonfatal stroke, and amputation. The hazard ratio for the primary end point in the intensive group was 0.47 (95% CI, 0.22 to 0.74; P=0.01). Reference: Gaede P, Vedel P, Larsen N, Jensen GV, Parving HH, Pedersen O. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med 2003;348:

Medicina Nuclear

Cintilografia Miocardica
Protocolo mais demorado Limitação do material Escolha da modalidade de estresse: - - esforço/dipiridamol/dobutamina Atenção para a frequencia cardíaca Sensibilidade 88% Acurácia similar em diabéticos e não diabéticos Intensive multiple risk factor management in patients with type 2 diabetes: STENO-2 The STENO-2 study randomized 160 patients (mean age of 55 years) with type 2 diabetes and microalbuminuria to targeted intensive multifactorial intervention or conventional treatment of cardiovascular risk factors for 8 years. The targeted intervention involved pharmacologic therapy and behavior modification targeting dyslipidemia, hyperglycemia, hypertension, microalbuminuria, and secondary prevention of cardiovascular disease with aspirin. The primary end point was a composite of nonfatal myocardial infarction, cardiovascular death, revascularization, nonfatal stroke, and amputation. The hazard ratio for the primary end point in the intensive group was 0.47 (95% CI, 0.22 to 0.74; P=0.01). Reference: Gaede P, Vedel P, Larsen N, Jensen GV, Parving HH, Pedersen O. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med 2003;348:

Diagnostic Accuracy of 64-Row Multidetector CT Angiography (MDCTA) for Patient- and Vessel-Based Detection of Coronary Stenosis of >=50% Table 4. Diagnostic Accuracy of 64-Row Multidetector CT Angiography (MDCTA) for Patient- and Vessel-Based Detection of Coronary Stenosis of >=50%. Miller J et al. N Engl J Med 2008;359:

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