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Epidemiología de la Resistencia a la Insulina, Diabetes Mellitus y Enfermedad Coronaria
 

Epidemiología de la Resistencia a la Insulina, Diabetes Mellitus y Enfermedad Coronaria

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  • Epidemiology of Insulin Resistance, Diabetes Mellitus, and Coronary Heart Disease <br />
  • Criteria for the Diagnosis of Diabetes Mellitus and Hyperglycemia: Plasma Glucose Concentration <br /> The diagnosis of type 2 diabetes mellitus, impaired glucose tolerance, and impaired fasting glucose is based on both the World Health Organization and the new American Diabetes Association (ADA) guidelines. According to these criteria, type 2 diabetes can be diagnosed by either by an oral glucose tolerance test with a 2-hour post-75-gram load value of 200 mg/dL or greater, or, what is more likely to occur in the United States, by a fasting glucose concentration of 126 mg/dL or greater. In addition, there are intermediate categories of glucose tolerance. Impaired glucose tolerance is diagnosed by a 2-hour postload oral glucose tolerance test of 140 mg/dL or greater and less than 200 mg/dL, and impaired fasting glucose is diagnosed by a fasting glucose of 110 mg/dL or greater and less than 126 mg/dL. Both people with impaired glucose tolerance and people with impaired fasting glucose have somewhat higher risk of cardiovascular disease than people with completely normal glucose tolerance tests, but the increases are only modest. Therefore, these categories have not been recognized as established risk factors by the National Cholesterol Education Program (NCEP) or the ADA. <br /> Reference: <br /> World Health Organization. Definition, Diagnosis and Classification of Diabetes Mellitus and Its Complications. Geneva: World Health Organization, 1999:52. <br />
  • Prevalence of Diabetes in Adult Population (Aged 20 years) by Year and Region <br /> This analysis, based on World Health Organization data, shows the increase in the prevalence of type 2 diabetes that is expected to occur in both the developed and the developing world. The rate of increase appears to be increasing, particularly in the developing world. <br /> Reference: <br /> King H, Aubert RE, Herman WH. Global burden of diabetes, 1995-2025: prevalence, numerical estimates, and projections. Diabetes Care 1998;21:1414-1431. <br />
  • Hospitalization Costs for Chronic Complications of Diabetes in the US <br /> These data from the ADA emphasize that 1) type 2 diabetes is extremely costly, and 2) cardiovascular disease constitutes 64% of total costs. <br /> Reference: <br /> American Diabetes Association. Economic Consequences of Diabetes Mellitus in the US in 1997. Alexandria, Va: American Diabetes Association, 1998:1-14. <br />
  • Framingham Study: DM and CHD Mortality: 20-Year Follow-up <br /> 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. <br /> Reference: <br /> Kannel WB, McGee DL. Diabetes and cardiovascular disease: the Framingham study. JAMA 1979;241:2035-2058. <br />
  • Mortality in People with Diabetes: Causes of Death <br /> 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. <br /> Reference: <br /> 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, 1995:233-257. <br />
  • Mortality Due to Heart Disease in Men and Women with or without Diabetes (US) <br /> 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; 1971-1975) were followed up for mortality through 1992-1993. Both heart disease mortality and ischemic heart disease mortality were much higher in diabetic subjects, men and women, than in people without diabetes. <br /> Reference: <br /> Gu K, Cowie CC, Harris MI. Mortality in adults with and without diabetes in a national cohort of the U.S. population, 1971-1993. Diabetes Care 1998;21:1138-1145. <br />
  • Trends in Mortality Rates for Ischemic Heart Disease in NHANES Subjects with and without Diabetes <br /> In a comparison of mean 9-year follow-up in participants in NHANES I, conducted in 1971-1975, and participants in the NHANES I Epidemiologic Follow-up Survey, conducted in 1982-1984, CHD mortality declined appreciably in nondiabetic men and women. In contrast, the decline among diabetic men was much smaller, and CHD mortality increased slightly in diabetic women, though the difference was not statistically significant. <br /> Reference: <br /> Gu K, Cowie CC, Harris MI. Diabetes and decline in heart disease mortality in US adults. JAMA 1999;281:1291-1297. <br />
  • Survival Post-MI in Diabetic and Nondiabetic Men and Women: Minnesota Heart Survey <br /> 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. <br /> Reference: <br /> 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;14:537-543. <br />
  • Cardiovascular Mortality in People with Diabetes <br /> The Finnish contribution to the World Health Organization Multinational Monitoring of Trends and Determinants of Cardiovascular Disease, FINMONICA, was different from most cardiologic studies in that it monitored prognosis from the beginning of symptoms, including out-of-hospital deaths, which occurred before admission to a hospital. In this study, mortality rates were again higher in diabetic men, who had a little more than a 50% 1-year case fatality rate, than in nondiabetic men, who had about a 35% 1-year case fatality rate. Mortality rates were also higher in diabetic women, who had a 45% case fatality rate, than in nondiabetic women, who had a 24% case fatality rate. However, the case fatality rate is higher in diabetic men than in diabetic women, which is somewhat unusual but can be understood by looking at when the deaths occurred. Time of death was divided into three periods: out-of-hospital deaths, deaths occurring within 28 days of hospitalization, and deaths occurring 28 days to 1 year after hospitalization. In diabetic men, out-of-hospital mortality was much higher than in diabetic women, suggesting that diabetic women may survive long enough to reach the hospital but then have much higher 28-day mortality. In fact, if out-of-hospital mortality is excluded, mortality rates from hospitalization to 1 year are higher in diabetic women than diabetic men, as was shown in the Minnesota Heart Study in the previous slide. Another interesting feature about the FINMONICA study is that it examined the prognosis of people having a first myocardial infarction. Given that diabetics have an increased rate of CHD and an increased case fatality rate, any diabetic who dies before reaching the hospital with a first myocardial infarction cannot possibly benefit from the secondary prevention program. This study was an important influence for the ADA&apos;s recommendation that perhaps all diabetics should be treated as if they have preexisting atherosclerosis. <br /> Reference: <br /> Miettinen H, Lehto S, Salomaa V, Mahonen M, Niemela M, Haffner SM, Pyorala K, Tuomilehto J, for the FINMONICA Myocardial Infarction Register Study Group. Impact of diabetes on mortality after the first myocardial infarction. Diabetes Care 1998;21:69-75. <br />
  • Influence of Multiple Risk Factors on CVD Death Rates in Diabetic and Nondiabetic Men: MRFIT Screenees <br /> 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 &gt;200 mg/dL, cigarette smoking, and systolic blood pressure &gt;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. <br /> Reference: <br /> 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;16:434-444. <br />
  • Putative Mechanism for Increased Atherosclerosis in Type 2 Diabetes <br /> A number of candidates have been proposed to contribute to the increased risk of CHD in diabetic patients. The precise importance of each of these mechanisms, however, is not at this point understood. <br /> Reference: <br /> Bierman EL. George Lyman Duff Memorial Lecture. Atherogenesis in diabetes. Arterioscler Thromb 1992;12:647-656. <br />
  • Prevalence of Cardiovascular Risk Factors in Diabetic Subjects Relative to Nondiabetics <br /> Compared with nondiabetics, patients with type I diabetes tend to have more hypertension and more hypertriglyceridemia but they do not have many of the disorders that are characteristic of patients with type 2 diabetes, such as low HDL cholesterol concentration, small dense LDL particles, increased apolipoprotein (apo) B concentration, and central obesity. Type 2 diabetics have more multiple metabolic abnormalities. While CHD rate is increased in both types of diabetes, the reason for the increase with type 1 diabetes is not clear. <br /> Reference: <br /> Chait A, Bierman EL. Pathogenesis of macrovascular disease in diabetes. In: Kahn CR, Weir GC, eds. Joslin&apos;s Diabetes Mellitus. 13th ed. Philadelphia: Lea & Febiger, 1994:648-664. <br />
  • Differences in HDL Cholesterol and LDL Size by Diabetic Status in Women and Men <br /> These results from the Strong Heart Study help to explain why the Framingham data show relatively higher rates of CHD mortality in diabetic women than diabetic men. Among women, HDL cholesterol was approximately 8 mg/dL lower in diabetics compared with nondiabetics, whereas among men, HDL cholesterol was about 4 mg/dL lower in diabetics compared with nondiabetics. Low HDL cholesterol may be important not only in explaining the very high risk of CHD in diabetic women, but also as a major risk factor in type 2 diabetes. A comparison of LDL particle size also indicates a relatively greater decrease with diabetes among women compared with men, but the difference is less dramatic than for HDL cholesterol. Smaller, denser LDL particles are believed by many to be more atherogenic. <br /> Reference: <br /> Howard BV, Cowan LD, Go O, Welty TK, Robbins DC, Lee ET. Adverse effects of diabetes on multiple cardiovascular disease risk factors in women: the Strong Heart Study. Diabetes Care 1998;21:1258-1265. <br />
  • Strategies for Reduction of Diabetic Complications <br /> Different treatment strategies may be needed for different types of diabetic complications. Microvascular complications of type 2 diabetes are generally considered to be diabetic renal disease, retinopathy, and neuropathy because glucose is so strongly related to these diabetic complications. To prevent these complications, it is not really necessary to prevent type 2 diabetes, but merely to screen aggressively for type 2 diabetes and improve metabolic control markedly in diagnosed patients. On the other hand, for macrovascular complications of type 2 diabetes, glucose is not as strongly related; therefore, a broad-based set of interventions is needed. Improved glycemic control may be important, although the relation between glycemic control and macrovascular complications appears to be fairly modest. Other strategies to reduce macrovascular complications include prevention of type 2 diabetes and aggressive treatment of established cardiovascular risk factors in diabetic subjects; in addition, some people believe that therapy should be intensified in prediabetic subjects as well. Lastly, prevention of macrovascular complications may include the use of diabetic agents that may preferentially improve cardiovascular risk factors, as some of the thiazolidinediones (TZDs) are thought to do. <br />
  • Incidence Rates of MI and Microvascular Endpoints by Mean Systolic Blood Pressure: UKPDS <br /> In the UK Prospective Diabetes Study (UKPDS), systolic blood pressure was equally related to both myocardial infarction and microvascular endpoints. <br /> Reference: <br /> 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;321:412-419. <br />
  • Incidence Rates of MI and Microvascular Endpoints by Mean Hemoglobin A1c: UKPDS <br /> 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. <br /> Reference: <br /> 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;321:405-412. <br />
  • Plasma Insulin and Triglycerides Predict Ischemic Heart Disease: Quebec Cardiovascular Study <br /> 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 (&lt;12 µU/ml), medium (12-15 µU/ml), and high (&gt;15 µU/ml) insulin levels and by low (&lt;150 mg/dL) and high (&gt;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. <br /> References: <br /> 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;334:952-957. <br /> 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;302:1383-1389. <br />
  • Plasma Insulin and Apolipoprotein B Predict Ischemic Heart Disease: Quebec Cardiovascular Study <br /> In the Quebec Cardiovascular Study, high insulin level was also predictive of CHD both in men with low apo B levels and in men with high apo B levels. However, whereas high triglyceride level did not further increase the CHD risk associated with high insulin level, high levels of apo B were strongly predictive of CHD: CHD risk was highest in men with elevations in both insulin and apo B. Therefore, to reduce CHD risk in diabetic patients, two interventions might be used simultaneously, one to lower apo B (such as a statin) and the other to improve insulin sensitivity. <br /> Reference: <br /> 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;334:952-957. <br />
  • LDL Particle Size and Apolipoprotein B Predict Ischemic Heart Disease: Quebec Cardiovascular Study <br /> In another analysis from the Quebec Cardiovascular Study, men were stratified by apo B level and LDL particle size. High apo B was associated with CHD, and the presence of both high apo B and small, dense LDL was associated with a marked increase in CHD risk. One interpretation of these findings is that concomitant interventions should be used both to lower apo B, such as with a statin, and to improve LDL particle size, such as with fibrates or high-dose statins. However, another interpretation is that if apo B is reduced to less than 120 mg/dL, LDL particle size no longer has an effect, perhaps because if there are few enough apo B-containing particles, it may not matter how atherogenic these particles are. This is a fairly controversial area, although a number of other epidemiological studies also suggest that this might be true. However, the effects of triglyceride level, for instance, which is strongly correlated to LDL particle size, appear to be considerably more important in people with high LDL/HDL ratio, apo B level, or total cholesterol level, as has been seen in the observational Paris Prospective Study and Prospective Cardiovascular Münster (PROCAM) Study and the interventional Helsinki Heart Study. <br /> Reference: <br /> Lamarche B, Tchernof A, Moorjani S, Cantin B, Dagenais GR, Lupien PJ, Despres JP. Small, dense low-density lipoprotein particles as a predictor of the risk of ischemic heart disease in men: prospective results from the Quebec Cardiovascular Study. Circulation 1997;95:69-75. <br />
  • Anthropometric Variables and Cardiovascular Risk Factors in Subjects with Normal Glucose Tolerance at Baseline According to Conversion Status at 8-Year Follow-up: San Antonio Heart Study <br /> In the San Antonio Heart Study, people with normal glucose tolerance were followed up to see whether they developed type 2 diabetes or remained nondiabetic. At baseline, those people who subsequently developed type 2 diabetes had higher triglyceride, lower HDL cholesterol, higher systolic blood pressure, and slightly higher glucose, but they had insulin concentrations almost twice as high as those in people who did not develop diabetes. Therefore, the working hypothesis is that hyperinsulemia and insulin resistance are responsible for driving this atherogenic prediabetic state. A more-recent analysis by the same group found that the atherogenic changes present in prediabetic patients were primarily due to insulin resistance rather than to decreased insulin secretion. <br /> References: <br /> 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. <br /> Haffner SM, Mykkanen L, Festa A, Burke JP, Stern MP. Insulin-resistant prediabetic subjects have more atherogenic risk factors than insulin-sensitive prediabetic subjects: implications for preventing coronary heart disease during the prediabetic state. Circulation 2000;101:975-980. <br />
  • &quot;Ticking Clock&quot; Hypothesis <br /> It has been suggested that for microvascular complications of diabetes, such as renal disease and retinopathy, the clock starts ticking, or the period of increased risk for diabetic complications begins, at the onset of hyperglycemia. Therefore, to prevent microvascular complications, prevention of type 2 diabetes is not really necessary, just early and aggressive treatment of diagnosed diabetes. However, for macrovascular complications of type 2 diabetes, like stroke or myocardial infarction, the period of increased risk begins, or the clock starts ticking, even before the onset of hyperglycemia. Therefore, prevention of type 2 diabetes and aggressive treatment of cardiovascular risk factors may be more important to prevent macrovascular complications. <br /> References: <br /> Diabetes Drafting Group. Prevalence of small vessel and large vessel disease in diabetic patients from 14 centres: the World Health Organisation Multinational Study of Vascular Disease in Diabetics. Diabetologia 1985;28 (suppl):615-640. <br /> 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. <br />
  • The 7-Year Age-Adjusted Incidence of CHD Mortality and All CHD Events: East-West Study <br /> The East-West Study is a prospective, population-based study of Finnish subjects, including more than 1,000 type 2 diabetics and almost 1,400 nondiabetics. This study showed that both fasting glucose and hemoglobin A1C predicted the incidence of CHD mortality and all CHD events. <br /> Reference: <br /> Lehto S, Ronnemaa T, Haffner SM, Pyorala K, Kallio V, Laakso M. Dyslipidemia and hyperglycemia predict coronary heart disease events in middle-aged patients with NIDDM. Diabetes 1997;46:1354-1359. <br />
  • Stepwise Selection of Risk Factors in 2693 White Patients with Type 2 Diabetes with Dependent Variable as Time to First Event: UKPDS <br /> In the large UKPDS, CHD risk factors were evaluated by their inclusion in a Cox proportional hazards model. In order, the variables included in the model were LDL cholesterol, HDL cholesterol, hemoglobin A1C, systolic blood pressure, and smoking. While hemoglobin A1C was highly statistically significant, so were conventional cardiovascular risk factors, the most important of which seem to be LDL and HDL. Triglyceride did not enter the multivariate analysis and was not a powerful predictor even when HDL was not in the model. In fact, preliminary data from UKPDS in which all the triglyceride levels were averaged across the 10-year trial suggest that triglyceride remains much less powerful than HDL. This finding challenges the earlier assumption that triglyceride level is a principal determinant of CHD in diabetics. <br /> Reference: <br /> Turner RC, Millns H, Neil HA, Stratton IM, Manley SE, Matthews DR, Holman RR. Risk factors for coronary artery disease in non-insulin dependent diabetes mellitus: United Kingdom Prospective Diabetes Study. BMJ 1998;316:823-828. <br />
  • Criteria for Accepting Cardiovascular Risk Factor Management as Similar in Diabetic and CHD Subjects <br /> Both the ADA position paper on diabetic dyslipidemia, which is updated each year, and the American Heart Association suggest that similar therapies should be used in diabetics and in CHD patients. The NCEP may also make this recommendation when the Adult Treatment Panel III guidelines are published in 2001. The rationale for this treatment strategy includes these three criteria, which have been substantiated by data from observational studies and clinical trials. <br />
  • 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 <br /> 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. <br /> References: <br /> 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;339:229-234. <br /> 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;102:1014-1019. <br />
  • Incidence of Fatal or Nonfatal Stroke During a 7-Year Follow-up in Relation to History of MI in Nondiabetic vs Diabetic Subjects: East-West Study <br /> Similar to the results for myocardial infarction, the East-West Study also found that diabetics with prior myocardial infarction had a higher incidence of stroke than diabetics without prior myocardial infarction. Stroke incidence in diabetics without prior myocardial infarction was 10.3%, compared with 7.2% in nondiabetics with prior myocardial infarction. <br /> Reference: <br /> 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;339:229-234. <br />
  • Conclusions <br />
  • Clinical Trials and Guidelines for Lipid Management in the Diabetic Patient <br />
  • UKPDS Design <br /> The UK Prospective Diabetes Study (UKPDS) was a pivotal clinical trial in type 2 diabetics, initially started in the 1970s. Almost 4,000 patients were randomized to conventional treatment with diet or to intensive treatment with a sulphonylurea (chlorpropamide, glibenclamide, or glipizide) and followed up for an average of about 10 years. The fundamental question was whether intensive glucose control reduced the risk of macrovascular and microvascular complications in patients with type 2 diabetes. <br /> References: <br /> UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837-853. <br /> Turner R, Cull C, Holman R. United Kingdom Prospective Diabetes Study 17: a 9-year update of a randomized, controlled trial on the effect of improved metabolic control on complications in non-insulin-dependent diabetes mellitus. Ann Intern Med 1996;124:136-145. <br />
  • UKPDS 10-Year Follow-up Results: Glycemic Control, Weight, and Plasma Insulin <br /> The results of UKPDS demonstrated that initially, intensive therapy with exogenous insulin or a sulphonylurea reduced hemoglobin A1c, but after 4-5 years, hemoglobin A1c increased at a rate similar to that in patients treated with conventional therapy. This finding demonstrates that there is progressive loss of glycemic control, which in other papers has been linked to progressive loss of beta cell function. If an intervention is withdrawn, then glycemic control gets worse, suggesting that it is not a loss of efficacy of a specific agent, but progressive loss due to the disease. The UKPDS results provide a rationale for the use of combination therapy when hemoglobin A1C and fasting glucose rise. This study also found that intensive control was associated with increased weight gain and increased risk for hypoglycemic episodes, which may be related to a diminution of the potential benefits of intensive glycemic control. <br /> Reference: <br /> UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837-853. <br />
  • UKPDS: Proportion of Patients Taking Different Therapies in the Conventional-Therapy Group <br /> UKPDS also suggested that over time, progressively more diabetic subjects may need additional pharmacologic agents. During the course of the study, more than 80% of subjects in the control group did need additional pharmacologic therapy. <br />
  • UKPDS: Causes of Death by Glucose Treatment Group <br /> In UKPDS, there were slightly lower death rates in the intensive treatment group than in the conventional treatment group, 17.8 per 1,000 patient-years as opposed to 18.7 per 1,000 patient-years. All macrovascular disease constituted a majority of cases in each group, 58% in the intensive treatment group and 60% in the conventional treatment group. Renal disease accounted for only 2% of deaths in the intensive treatment group and 1% in the conventional treatment group. These results show that even among new diabetics, during the first 10 years after diagnosis, macrovascular disease dominates the causes of death. <br /> Reference: <br /> UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837-853. <br />
  • UKPDS: Endpoints by Glucose Treatment Group <br /> Among the primary endpoints in UKPDS, there was a 12% reduction in risk for any diabetes-related event, which was significant at p=0.029. The reduction in risk for myocardial infarction was relatively modest at 16%, which was not quite statistically significant at p=0.052. The large 25% reduction in microvascular disease is consistent with the updated hemoglobin A1C data from UKPDS included in the Epidemiology module of this slide set (slide 17). <br /> Reference: <br /> UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837-853. <br />
  • UKPDS: Impact of Glucose-Lowering Agents on MI and Stroke <br /> In UKPDS patients randomized to intensive therapy with a sulphonylurea or exogenous insulin, there was a 16% reduction in myocardial infarction and an 11% increase in stroke, though the numbers for the latter are very small. Overweight patients were randomized to a metformin group in addition to the two intensive therapy groups or the conventional therapy group; the metformin group had a very impressive 39% reduction in myocardial infarction, and a 41% reduction in stroke. In a supplementary study of overweight and nonoverweight patients randomized to sulphonylurea therapy with or without metformin, patients treated with both metformin and a sulphonylurea had a statistically significant 96% increase in risk of diabetes-related death compared with patients treated with a sulphonylurea alone. Most diabetologists believe that this combination metformin-sulphonylurea group was aberrant. A combined analysis of the main UKPDS and the supplementary study found a significant 19% reduction in risk for diabetes-related endpoints with metformin. <br /> References: <br /> UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837-853. <br /> UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998;352:854-865. <br />
  • UKPDS Results: Intensive Blood Pressure Control <br /> Approximately 1,100 subjects out of the 4,000 subjects in the UKPDS were randomized either to intensive blood pressure control with an angiotensin-converting enzyme (ACE) inhibitor or a beta-blocker or to less-intensive blood pressure control. At 9-year follow-up, systolic blood pressure was a mean 10 mm Hg lower and diastolic blood pressure was a mean 5 mm Hg lower with intensive control compared with less-intensive control. In contrast to the results of glycemic control, intensive blood pressure control in the UKPDS was associated with significant reductions in macrovascular disease, specifically stroke, as well as a nonsignificant 21% decline in myocardial infarction, which was larger than in the comparison of glycemic interventions. Intensive blood pressure control also reduced microvascular disease endpoints by 37%. Some investigators have interpreted these results as suggesting that blood pressure reduction is more important than glycemic control in diabetic patients. However, this is not quite a correct interpretation, because there were many fewer people in the blood pressure study than in the glycemic control study. In addition, in unpublished data, those individuals who were randomized to both intensive blood pressure control and intensive glycemic control had the best results of all. <br /> Reference: <br /> UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ 1998;317:703-713. <br />
  • Comparison of Captopril vs. Atenolol in UKPDS <br /> Approximately 350 people in the UKPDS were randomized to usual care, 350 to captopril, and 350 to atenolol. There was no significant difference between captopril and atenolol, suggesting that beta-blockers work just as well as, in fact, perhaps even a little bit better than, ACE inhibitors. However, the number of subjects is relatively small, and other data, such as those from the Heart Outcomes Prevention Evaluation (HOPE) study, show that an ACE inhibitor provided significant benefits on coronary heart disease (CHD) endpoints even among diabetics. In addition, in the Microalbuminuria, Cardiovascular, and Renal Outcomes (MICRO) HOPE substudy, an ACE inhibitor (ramipril) also reduced risk for overt nephropathy. <br /> References: <br /> UK Prospective Diabetes Study Group. Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39. BMJ 1998;317:713-720. <br /> Heart Outcomes Prevention Evaluation Study Investigators. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO‑HOPE substudy. Lancet 2000;355:253-259. <br />
  • Comparison of Glucose Lowering and Blood Pressure Lowering in UKPDS <br /> The results of intensive glucose control and intensive blood pressure control in the UKPDS are combined to facilitate the comparison of the relative benefits of glucose-lowering and blood pressure-lowering on clinical endpoints in that study. <br /> References: <br /> UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837-853. <br /> UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ 1998;317:703-713. <br />
  • Treatment Strategies for Diabetic Dyslipidemia <br /> According to the American Diabetes Association (ADA), the primary strategy in the treatment of diabetic dyslipidemia is to lower low-density lipoprotein (LDL) cholesterol, and the secondary strategy is to raise high-density lipoprotein (HDL) cholesterol and lower triglycerides. In addition, there are a number of other approaches, including reducing non-HDL cholesterol, which will probably be adopted as a secondary target by the National Cholesterol Education Program (NCEP) in their Adult Treatment Panel III recommendations. A number of investigators believe that apolipoprotein (apo) B may be even a better target than LDL cholesterol, but the measurement of apo B is not sufficiently standardized, at least according to the NCEP. A number of individuals also think that remnants may be better predictors of CHD, but lack of standardization of measurement presents potential problems with this target as well. <br /> References: <br /> American Diabetes Association. Management of dyslipidemia in adults with diabetes. Diabetes Care 2000;23 (suppl 1):S57-S60. <br /> Chait A, Brunzell JD. Diabetes, lipids, and atherosclerosis. In: LeRoith D, Taylor SI, Olefsky JM, eds. Diabetes Mellitus: a Fundamental and Clinical Text. Philadelphia: Lippincott-Raven, 1996:772-779. <br /> European Diabetes Policy Group 1999. A desktop guide to Type 2 diabetes mellitus. Diabet Med 1999;16:716-730. <br />
  • CHD Prevention Trials with Statins in Diabetic Subjects: Subgroup Analyses <br /> Primary and secondary prevention trials of statin therapy have included a fairly large number of diabetic subjects. Mean baseline LDL cholesterol levels for the various trials have ranged from a low of 136 mg/dL in CARE to 186 mg/dL in the Scandinavian Simvastatin Survival Study (4S), and the degree of LDL cholesterol lowering has ranged from 25% in the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) and the Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) to 36% in 4S. <br /> References: <br /> Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA, Langendorfer A, Stein EA, Kruyer W, Gotto AM Jr, for the AFCAPS/TexCAPS Research Group. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. JAMA 1998;279:1615-1622. <br /> 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. <br /> 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;20:614-620. <br /> Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med 1998;339:1349-1357. <br /> Haffner SM, Alexander CM, Cook TJ, Boccuzzi SJ, Musliner TA, Pedersen TR, Kjekshus J, Pyorala K, for the Scandinavian Simvastatin Survival Study Group. Reduced coronary events in simvastatin-treated patients with coronary heart disease and diabetes or impaired fasting glucose levels: subgroup analyses in the Scandinavian Simvastatin Survival Study. Arch Intern Med 1999;159:2661-2667. <br />
  • CHD Prevention Trials with Statins in Diabetic Subjects: Subgroup Analyses (continued) <br /> CHD risk reduction among diabetic subjects was greater in 4S and AFCAPS/TexCAPS than in CARE and LIPID. Perhaps more importantly, CHD risk reduction in the overall study groups was comparable or even less than in the diabetic subgroups, which is important in establishing a criteria for similar therapy in diabetics and in CHD patients. There is certainly no evidence that statin therapy is any less effective in diabetic patients than in patients without diabetes. <br /> References: <br /> Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA, Langendorfer A, Stein EA, Kruyer W, Gotto AM Jr, for the AFCAPS/TexCAPS Research Group. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. JAMA 1998;279:1615-1622. <br /> 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. <br /> 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;20:614-620. <br /> Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med 1998;339:1349-1357. <br /> Haffner SM, Alexander CM, Cook TJ, Boccuzzi SJ, Musliner TA, Pedersen TR, Kjekshus J, Pyorala K, for the Scandinavian Simvastatin Survival Study Group. Reduced coronary events in simvastatin-treated patients with coronary heart disease and diabetes or impaired fasting glucose levels: subgroup analyses in the Scandinavian Simvastatin Survival Study. Arch Intern Med 1999;159:2661-2667. <br />
  • Diabetic vs. Nondiabetic Patients in 4S <br /> 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. <br /> Reference: <br /> 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;20:614-620. <br />
  • Major Coronary Events in 4S Patients with or without Diabetes by History (n=202) <br /> 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. <br /> Reference: <br /> 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;20:614-620. <br />
  • 4S: Extended Diabetic Subgroup Analysis: Diabetes (n=483; 251 on Simvastatin)—Fasting Glucose 7 mmol/L (126 mg/dl) <br /> Another subgroup analysis of 4S used the revised ADA criteria for diabetes and impaired fasting glucose instead of prior clinical diagnosis of diabetes. The number of type 2 diabetics, characterized by a fasting glucose of 126 mg/dL or more, therefore was increased from 202 to 483 subjects, and thus had greater generalizability. In this analysis, simvastatin therapy was associated with a 42% reduction in major coronary events such as fatal and nonfatal MI, and there was also a significant 48% reduction in revascularizations. In addition, there were tendencies toward reductions in CHD mortality and total mortality. <br /> Reference: <br /> Haffner SM, Alexander CM, Cook TJ, Boccuzzi SJ, Musliner TA, Pedersen TR, Kjekshus J, Pyorala K, for the Scandinavian Simvastatin Survival Study Group. Reduced coronary events in simvastatin-treated patients with coronary heart disease and diabetes or impaired fasting glucose levels: subgroup analyses in the Scandinavian Simvastatin Survival Study. Arch Intern Med 1999;159:2661-2667. <br />
  • 4S: Extended Diabetic Subgroup Analysis: Impaired Fasting Glucose (n=678; 343 on Simvastatin)—Fasting Glucose 6.0–6.9 mmol/L (110–125 mg/dl) <br /> Impaired fasting glucose is defined in the ADA guidelines as a fasting glucose level between 110 mg/dL and 125 mg/dL. Individuals with impaired fasting glucose do not have diabetes at this point, but they are at high risk for developing type 2 diabetes. They tend to be insulin resistant, with low HDL cholesterol levels. A large group of such patients, 678 subjects, were identified in 4S, constituting approximately 15% of all subjects in 4S. These were in addition to the 11% with type 2 diabetes. This is particularly impressive because 4S patients had CHD with high LDL cholesterol levels, suggesting that even more patients with diabetes and impaired fasting glucose would be included in a group of CHD patients who have lower LDL cholesterol levels. In this analysis, simvastatin therapy was associated with significant reductions in all four major endpoints: major coronary events, revascularizations, total mortality, and CHD mortality. <br /> Reference: <br /> Haffner SM, Alexander CM, Cook TJ, Boccuzzi SJ, Musliner TA, Pedersen TR, Kjekshus J, Pyorala K, for the Scandinavian Simvastatin Survival Study Group. Reduced coronary events in simvastatin-treated patients with coronary heart disease and diabetes or impaired fasting glucose levels: subgroup analyses in the Scandinavian Simvastatin Survival Study. Arch Intern Med 1999;159:2661-2667. <br />
  • 4S: Effect of Statin Therapy on Hospital Stay <br /> In an economic analysis of the effect of simvastatin on hospital stay in 4S, there was a 55% reduction with simvastatin therapy in patients with diabetes (using the ADA criterion), a 38% reduction in patients with impaired fasting glucose, and a 28% reduction in patients with normal fasting glucose. This suggests that the economic benefit of simvastatin therapy is, if anything, somewhat greater in patients with diabetes or impaired fasting glucose than in nondiabetic patients. This analysis also found that the cost of medical care in diabetics in 4S was lower in the simvastatin group than in the placebo group, because the reduction in hospitalization was so great it offset the increased cost of medical therapy for simvastatin. <br /> Reference: <br /> Herman WH, Alexander CM, Cook JR, Boccuzzi SJ, Musliner TA, Pedersen TR, Kjekshus J, Pyorala K, for the Scandinavian Simvastatin Survival Study Group. Effect of simvastatin treatment on cardiovascular resource utilization in impaired fasting glucose and diabetes. Findings from the Scandinavian Simvastatin Survival Study. Diabetes Care 1999;22:1771-1778. <br />
  • CARE: Major Coronary Events in Diabetic Subgroups <br /> 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. <br /> Reference: <br /> 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. <br />
  • AFCAPS/TexCAPS: Subgroup Analysis <br /> In AFCAPS/TexCAPS, a primary-prevention trial, there were only approximately 250 diabetics. As a result, the 42% reduction in risk for a major coronary event in these patients was not statistically significant, but was comparable to the 37% reduction in AFCAPS/TexCAPS in the overall study population. <br /> Reference: <br /> Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA, Langendorfer A, Stein EA, Kruyer W, Gotto AM Jr, for the AFCAPS/TexCAPS Research Group. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. JAMA 1998;279:1615-1622. <br />
  • CARE: Major Coronary Events in Diabetic Subgroups <br /> 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. <br /> Reference: <br /> 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. <br />
  • Post-CABG: Effect of Aggressive Lipid Lowering on Progression in a Diabetic Subgroup <br /> The Post Coronary Artery Bypass Graft study (Post-CABG) randomized individuals with prior CABG to either aggressive lovastatin therapy or moderate lovastatin therapy. The LDL cholesterol levels achieved in the respective groups were 95 mg/dL versus 135 mg/dL. In the overall paper, there was a significant slowing of angiographic progression of atherosclerosis in saphenous vein grafts in the high-dose lovastatin group compared with the low-dose lovastatin group. A subgroup analysis of diabetic subjects in Post-CABG showed a 51% reduction in progression in the diabetics as opposed to a 40% reduction in the nondiabetics. Thus, although diabetics do not have particularly high LDL cholesterol levels, they benefit just as much from aggressive LDL cholesterol reduction as do nondiabetics. The clinical trial data provide strong support for an LDL cholesterol goal of 100 mg/dL in diabetic patients. <br /> Reference: <br /> Hoogwerf BJ, Waness A, Cressman M, Canner J, Campeau L, Domanski M, Geller N, Herd A, Hickey A, Hunninghake DB, Knatterud GL, White C. Effects of aggressive cholesterol lowering and low-dose anticoagulation on clinical and angiographic outcomes in patients with diabetes: the Post Coronary Artery Bypass Graft Trial. Diabetes 1999;48:1289-1294. <br />
  • CHD Prevention Trials with Fibrates in Diabetic Subjects: Subgroup Analyses <br /> Trials of fibrate therapy that included diabetic subgroups were the primary-prevention Helsinki Heart Study and the secondary-prevention Veterans Affairs HDL Intervention Trial (VA-HIT). There were only 135 diabetic patients in the Helsinki Heart Study, and the CHD reduction was 68%, which was not statistically significant because of low power. VA-HIT had a much larger number of diabetic subjects, and this subgroup had a statistically significant 24% reduction in CHD events. In VA-HIT, mean baseline LDL cholesterol was only about 112 mg/dL; HDL cholesterol was also low at 32 mg/dL, and triglyceride levels were modest at 160 mg/dL. Gemfibrozil produced relatively little LDL cholesterol change in either study. In VA-HIT, HDL cholesterol was increased by about 6% and triglyceride was reduced by about 30% <br /> References: <br /> Koskinen P, Mänttäri M, Manninen V, Huttunen JK, Heinonen OP, Frick MH. Coronary heart disease incidence in NIDDM patients in the Helsinki Heart Study. Diabetes Care 1992;15:820-825. <br /> Rubins HB, Robins SJ, Collins D, Fye CL, Anderson JW, Elam MB, Faas FH, Linares E, Schaefer EJ, Schectman G, Wilt TJ, Wittes J, for the Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. N Engl J Med 1999;341:410-418. <br />
  • Primary CHD Prevention in Type 2 Diabetic Patients: The Helsinki Heart Study <br /> Among patients with type 2 diabetes in the Helsinki Heart Study, there was an appreciable decline in CHD events with gemfibrozil, but these results were not statistically significant. In the placebo group, the type 2 diabetics had a much higher event rates than nondiabetics. <br /> Reference: <br /> Koskinen P, Mänttäri M, Manninen V, Huttunen JK, Heinonen OP, Frick MH. Coronary heart disease incidence in NIDDM patients in the Helsinki Heart Study. Diabetes Care 1992;15:820-825. <br />
  • VA-HIT: Incidence of Death from CHD and Nonfatal MI <br /> In the overall study population of VA-HIT, CHD death and nonfatal myocardial infarction were significantly reduced with gemfibrozil. Separation of the Kaplan-Meier curve occurred sometime between the first and second year of the study. <br /> Reference: <br /> Rubins HB, Robins SJ, Collins D, Fye CL, Anderson JW, Elam MB, Faas FH, Linares E, Schaefer EJ, Schectman G, Wilt TJ, Wittes J, for the Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. N Engl J Med 1999;341:410-418. <br />
  • VA-HIT: Death Due to CHD, Nonfatal MI, and Confirmed Stroke in Diabetic Patients <br /> In a subgroup analysis of VA-HIT, there was a 24% reduction in cardiovascular disease events in diabetic patients, which was the same as in nondiabetic patients. <br /> Reference: <br /> Rubins HB, Robins SJ, Collins D, Fye CL, Anderson JW, Elam MB, Faas FH, Linares E, Schaefer EJ, Schectman G, Wilt TJ, Wittes J, for the Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. N Engl J Med 1999;341:410-418. <br />
  • Future Directions <br /> A number of studies in diabetic patients are under way. The Diabetes Atherosclerosis Intervention Study (DAIS), which used 200 mg of micronized fenofibrate, was presented by Dr. George Steiner at the International Atherosclerosis Society meeting in Stockholm in June 2000 but has not yet been published. This study included 418 diabetic subjects and showed about a 25% reduction in CHD, which was not statistically significant. In two of the three endpoints for angiography, there were significant reductions in progression of disease. <br />
  • Heart Protection Study <br /> The Heart Protection Study includes about 20,000 CHD patients in the UK and has a 2x2 factorial design: simvastatin 40 mg versus placebo, and an antioxidant cocktail of vitamin E, vitamin C, and beta carotene versus placebo. There were about 6,000 diabetic subjects, of whom 4,000 had not had a prior event. This study should be reported in December 2001 and may provide important information on whether statins decrease the incidence of CHD in diabetics without previous clinical disease. <br /> Reference: <br /> MRC/BHF Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol-lowering therapy and of antioxidant vitamin supplementation in a wide range of patients at increased risk of coronary heart disease death: early safety and efficacy experience. Eur Heart J 1999;20:725-741. <br />
  • Endpoint Studies: Treating to New Targets (TNT): Study Design <br /> Treating to New Targets (TNT) enrolled approximately 10,000 CHD patients and is scheduled to be completed in December 2004. Patients are treated to different goals to compare the conventional NCEP guideline of an LDL cholesterol goal of less than 100 mg/dL with a more aggressive LDL cholesterol goal of less than 75 mg/dL. The interventions used are atorvastatin 10 mg/day versus atorvastatin 80 mg/day. This study contains a fairly sizable number of type 2 diabetics, so it may provide some important information on the appropriate target in these individuals as well. <br />
  • Study of the Effectiveness of Additional Reduction in Cholesterol and Homocysteine with Simvastatin and Folic Acid/Vitamin B12 (SEARCH): Study Design <br /> The Study of the Effectiveness of Additional Reduction in Cholesterol and Homocysteine with Simvastatin and Folic Acid/Vitamin B12 (SEARCH) compares the intensity of lipid lowering, rather than specific goals, in 12,000 subjects who have had a prior MI. The lipid-lowering interventions tested are simvastatin 20 mg/day, which was used in about two-thirds of the patients in 4S, versus simvastatin 80 mg/day. In addition, SEARCH is testing the homocysteine hypothesis by the use of 2 mg of folic acid and 1 mg of vitamin B12. <br />
  • Lipids in Diabetes Study (LDS): Two-by-Two Factorial Randomization <br /> The Lipids in Diabetes Study (LDS), under way in the UK, included only diabetic subjects without a prior MI. In the 2x2 factorial design, 5,000 patients were randomized to cerivastatin 0.4 mg versus placebo and micronized fenofibrate 200 mg or placebo. This study will directly compare the benefits of cerivastatin versus fenofibrate, and will also measure LDL particle size with NMR to determine whether fibrates or statins work better or worse in patients with particular LDL phenotypes. Evaluation of the 1,250 subjects on both cerivastatin and fenofibrate will provide good evidence on the safety as well as the additional efficacy of adding a fibrate to a statin, although the study is not fully powered for this. This study presents an alternate model for treating beyond the NCEP guidelines, by adding a fibrate to a statin as opposed to further LDL cholesterol lowering with higher-dose statin as in SEARCH and TNT. <br />
  • Conclusions <br />
  • Clinical Evaluation and Nonlipid Treatment of Coronary Artery Disease in the Diabetic Patient <br />
  • Prevalence of Asymptomatic CAD in Diabetes Mellitus <br /> 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. <br /> References: <br /> Koistinen MJ. Prevalence of asymptomatic myocardial ischaemia in diabetic subjects. BMJ 1990;301:92-95. <br /> 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. <br /> 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;79:134-139. <br /> 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. <br /> 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. <br /> 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;90:563-570. <br />
  • Indications for Cardiac Testing in Diabetic Patients <br /> 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. <br />
  • Factors Limiting Accuracy of Noninvasive &quot;Stress&quot; Tests for CAD <br /> 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. <br />
  • Benefits of Early Detection of CAD <br /> 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. <br />
  • Blood Pressure and CVD: Framingham Heart Study <br /> In the Framingham Heart Study, at any level of blood pressure the risk for a cardiac event was higher in both men and women with glucose intolerance compared with the risk level in the absence of glucose intolerance. The risk for cardiovascular events in both sexes increased linearly in the “normotensive” blood pressure range and extending into the range of blood pressure levels usually considered “hypertensive.” These data support the notion that intensive blood pressure lowering in patients with diabetes would lead to reductions in the risk for cardiovascular events. These data also support lowering of the target blood pressure from 140/90 to 130/85 mm Hg in patients with diabetes. <br /> Reference: <br /> Kannel WB, Wilson PW, Zhang TJ. The epidemiology of impaired glucose tolerance and hypertension. Am Heart J 1991;121:1268-1273. <br />
  • Effect of Glycemic Control in the UK Prospective Diabetes Study (UKPDS) <br /> The UK Prospective Diabetes Study (UKPDS) compared the benefits of intensive glycemic control versus conventional glycemic control in reduction of diabetes-related endpoints. The major benefit was in the reduction of microvascular endpoints. Myocardial infarction was reduced by 16%, but this reduction did not achieve statistical significance. There was no statistically significant reduction in the incidence of stroke or peripheral vascular disease in the intensively treated group compared with the group treated with conventional glycemic control. UKPDS showed that glycemic control management in the context of a clinical trial did not necessarily result in the reduction of macrovascular events, but primarily reduced microvascular endpoints in patients with diabetes. <br /> Reference: <br /> UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837-853. <br />
  • Reasons for Death in UKPDS Intensive Treatment Arm: 10-Year Follow-up <br /> Patients enrolled in UKPDS were newly diagnosed type 2 diabetic patients with a relatively low prevalence of background risk factors and no prior history of cardiovascular disease. In the intensive glucose control arm during the first 10 years, 8.4% of the patients died of either fatal myocardial infarction or sudden death, signifying the importance of coronary heart disease as a primary determinant outcome even in patients with tight glycemic control managed in a clinical trial. <br /> Reference: <br /> UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837-853. <br />
  • Effect of Blood Pressure Control in the UKPDS: Tight vs. Less Tight Control <br /> In the UKPDS, a subgroup of patients with type 2 diabetes mellitus was randomized to either “tight” blood pressure control, in which blood pressure was lowered to a mean of 144/82 mm Hg, or to “loose” control, in which blood pressure was lowered to a mean of 154/87 mm Hg. Patients were also randomized to captopril or atenolol, with diuretics added to achieve target blood pressure levels, and were followed up for 9 years. <br /> Tight blood pressure control led to a significant reduction in diabetes-related endpoints, including diabetes-related deaths and complications related to microvascular disease. Heart failure and stroke were remarkably reduced. There was a trend toward a reduction of myocardial infarction, with a risk reduction of 21%, but it did not achieve statistical significance. <br /> Reference: <br /> UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ 1998;317:703-713. <br />
  • UKPDS: ACE Inhibitor vs. Beta-blocker for HTN: Aggregate Clinical Endpoints <br /> Patients in the UKPDS randomized to tight blood pressure control were also randomized to primary therapy with the angiotensin-converting enzyme (ACE) inhibitor captopril or the beta-blocker atenolol. There was no difference in benefit with regard to reduction of either diabetes-related endpoints or macrovascular events with either ACE inhibitor or beta-blocker treatment. This study indicates that blood pressure lowering, regardless of the type of agent used, will result in a reduction of microvascular disease, heart failure, and stroke. <br /> Reference: <br /> UK Prospective Diabetes Study Group. Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39. BMJ 1998;317:713-720. <br />
  • Systolic Hypertension in Europe (Syst-Eur) Trial: Effect of Systolic BP Control on All Cardiovascular Events at 2 Years <br /> The Systolic Hypertension in Europe (Syst-Eur) Trial is another study that evaluated the benefits of any hypertensive treatment in patients with systolic hypertension. Patients were randomized to active treatment based on nitrendipine, with ACE inhibitors, beta-blockers, and diuretics added to achieve target blood pressure goals. Patients with diabetes mellitus had a 62% risk reduction in cardiovascular events at 2 years, whereas patients without diabetes mellitus had a 25% risk reduction. The Syst-Eur Trial provides additional data on the importance of blood pressure lowering, particularly in patients with diabetes, whose baseline risk is higher. <br /> Reference: <br /> Tuomilehto J, Rastenyte D, Birkenhager WH, Thijs L, Antikainen R, Bulpitt CJ, Fletcher AE, Forette F, Goldhaber A, Palatini P, Sarti C, Fagard R, for the Systolic Hypertension in Europe Trial Investigators. Effects of calcium-channel blockade in older patients with diabetes and systolic hypertension. N Engl J Med 1999;340:677-684. <br />
  • Major Outcomes of the Hypertension Optimal Treatment (HOT) Trial: Diabetes Subgroup <br /> In the Hypertension Optimal Treatment (HOT) Trial, more than 19,000 patients were randomized to 3 different target blood pressure levels (less than or equal to 90 mm Hg, less than or equal to 85 mm Hg, or less than or equal to 80 mm Hg) and treated with a long-acting calcium antagonist, felodipine. ACE inhibitors, beta-blockers, and diuretics were added to reach target blood pressure levels in each of the 3 groups as needed. In the 1,501 patients with diabetes mellitus, the risk for a major cardiovascular event or myocardial infarction was lowest in the group randomized to a target blood pressure of less than or equal to 80 mm Hg. Despite the small difference in diastolic target blood pressures, there was a substantial benefit as blood pressure was lowered with treatment in the patients with diabetes mellitus. These data also support the benefits of intensive blood pressure lowering in diabetic patients with hypertension. <br /> Reference: <br /> 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;351:1755-1762. <br />
  • HOT Trial: Cardiovascular Events in Diabetics and Nondiabetics—Effect of Diastolic Target at 4 Years <br /> 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. <br /> Reference: <br /> 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;351:1755-1762. <br />
  • Completed Clinical Trials with Antihypertensive Agents in Diabetes <br /> In addition to the UKPDS, Syst-Eur, and HOT studies already discussed, several other trials such as Systolic Hypertension in the Elderly Program (SHEP), Grupo Italiano per lo Studio della Sopravvivenza nell&apos;Infarto Miocardico 3 (GISSI-3), and Captopril Prevention Project (CAPPP) have also shown the benefits of blood pressure reduction in diabetics. In summary, there is a wealth of evidence to support the benefit of blood pressure control in patients with diabetes, and combination therapy is frequently required to achieve the goal established by the sixth report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI) to reduce blood pressure to &lt;130/85 mm Hg. <br /> References: <br /> Curb JD, Pressel SL, Cutler JA, Savage PJ, Applegate WB, Black H, Camel G, Davis BR, Frost PH, Gonzalez N, Guthrie G, Oberman A, Rutan GH, Stamler J, for the Systolic Hypertension in the Elderly Program Cooperative Research Group. Effect of diuretic-based antihypertensive treatment on cardiovascular disease risk in older diabetic patients with isolated systolic hypertension. JAMA 1996;276:1886-1892. <br /> Zuanetti G, Latini R, Maggioni AP, Franzosi M, Santoro L, Tognoni G. Effect of the ACE inhibitor lisinopril on mortality in diabetic patients with acute myocardial infarction: data from the GISSI-3 study. Circulation 1997;96:4239-4245. <br /> Staessen JA, Thijs L, Gasowski J, Cells H, Fagard RH. Treatment of isolated systolic hypertension in the elderly: further evidence from the Systolic Hypertension in Europe (Syst-Eur) trial. Am J Cardiol 1998;82:20R-22R. <br /> 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;351:1755-1762. <br /> UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ 1998;317:703-713. <br /> Hansson L, Lindholm LH, Niskanen L, Lanke J, Hedner T, Niklason A, Luomanmaki K, Dahlof B, de Faire U, Morlin C, Karlberg BE, Wester PO, Bjorck JE. Effect of angiotensin-converting-enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: the Captopril Prevention Project (CAPPP) randomised trial. Lancet 1999;353:611-616. <br />
  • Heart Outcomes Prevention Evaluation (HOPE) Study: Effect of Ramipril on Cardiovascular Events (Myocardial Infarction, Stroke, or CVD Death) ~4.5 Yrs <br /> 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. <br /> Reference: <br /> 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;342:145-153. <br />
  • Diabetes Increases Risk of Coronary Plaque Disruption and Thrombosis: Cause of Myocardial Infarction <br /> 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. <br />
  • Impact of Serum Fibrinogen and Total Cholesterol Levels: Two Year Follow-up – Risk of Coronary Events in ECAT <br /> In the European Concerted Action on Thrombosis and Disabilities (ECAT) Angina Pectoris Study, the risk for coronary events was related to tertiles of fibrinogen and cholesterol levels in patients with modest coronary artery disease. As seen in the graph, the risk for coronary events was lowest in the individuals whose fibrinogen level was in the lowest tertile, regardless of the level of cholesterol. <br /> Reference: <br /> Thompson SG, Kienast J, Pyke SD, Haverkate F, van de Loo JC, for the European Concerted Action on Thrombosis and Disabilities Angina Pectoris Study Group. Hemostatic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. N Engl J Med 1995;332:635-641. <br />
  • Effect of Aspirin on Mortality in Type 2 Patients with CHD: Bezafibrate Infarction Prevention Study <br /> 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. <br /> Reference: <br /> 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;105:494-499. <br />
  • Antiplatelet Agents Reduce CVD Events in Patients with Diabetes: Antiplatelet Trialists&apos; Collaboration <br /> In the Antiplatelet Trialists&apos; 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. <br /> Reference: <br /> Antiplatelet Trialists&apos; 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;308:81-106. <br />
  • Diabetes Mellitus Insulin Glucose Infusion in Acute Myocardial Infarction (DIGAMI): Benefit of Tight Glycemic Control in No Insulin–Low Risk Cohort <br /> The Diabetes Mellitus Insulin Glucose Infusion in Acute Myocardial Infarction (DIGAMI) Study was performed in Scandinavia and randomized patients with diabetes mellitus with acute myocardial infarction to two different glycemic control strategies. One group was treated with “ad hoc” glycemic control and the other group was treated with intensive glycemic control with intravenous insulin therapy for at least 24 hours followed by 3 months of multidose daily insulin. The group randomized to tight glycemic control had a significant reduction in mortality evident at 3 years. Most of the benefit in the tightly controlled group was due to benefit in diabetic patients who were not on insulin therapy at the time of randomization. Tight glycemic control in a setting of acute myocardial infarction may reduce platelet aggregability, alter lipoprotein metabolism, reduce free fatty acid levels, restore fibrinolysis, change the sympathetic and parasympathetic balance, and improve myocardial energy metabolism. <br /> Reference: <br /> Malmberg K, for the DIGAMI (Diabetes Mellitus, Insulin Glucose Infusion in Acute Myocardial Infarction) Study Group. Prospective randomised study of intensive insulin treatment on long term survival after acute myocardial infarction in patients with diabetes mellitus. BMJ 1997;314:1512-1515. <br />
  • Effect of Trandolapril on Post-MI CHF Progression: Trandolapril Cardiac Evaluation (TRACE) <br /> The Trandolapril Cardiac Evaluation (TRACE) study was a randomized, double-blind trial that included 1749 patients with left ventricular ejection fraction less than or equal to 35% who were treated with trandolapril versus placebo started between 3 and 7 days post acute myocardial infarction. The 234 patients with diabetes had a much higher absolute risk for progression to severe or resistant congestive heart failure, with a marked reduction in relative risk ( 0.38, p&lt;0.001). Patients without diabetes were less likely to have progression and also had less of a reduction in relative risk (0.81, p=0.1). <br /> Reference: <br /> Gustafsson I, Torp-Pedersen C, Kober L, Gustafsson F, Hildebrandt P, on behalf of the TRACE Study Group. Effect of the angiotensin-converting enzyme inhibitor trandolapril on mortality and morbidity in diabetic patients with left ventricular dysfunction after acute myocardial infarction. J Am Coll Cardiol 1999;34:83-89. <br />
  • Effect of Trandolapril on Secondary Endpoints in TRACE <br /> In the TRACE study, 126 patients (53%) of the diabetic group died compared with 547 (36%) of the nondiabetic group. Diabetic patients tended to have greater reductions in relative risk for all cardiovascular endpoints, and the interaction between benefit from treatment with trandolapril and diabetes was statistically significant (p=0.03). In summary, diabetic patients with acute myocardial infarction and left ventricular dysfunction tend to have a higher risk for left ventricular remodeling and progression to severe heart failure and merit early initiation with ACE inhibitors post myocardial infarction. <br /> Reference: <br /> Gustafsson I, Torp-Pedersen C, Kober L, Gustafsson F, Hildebrandt P, on behalf of the TRACE Study Group. Effect of the angiotensin-converting enzyme inhibitor trandolapril on mortality and morbidity in diabetic patients with left ventricular dysfunction after acute myocardial infarction. J Am Coll Cardiol 1999;34:83-89. <br />
  • Effect of Diabetes on 30-Day Mortality: Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO-I) <br /> The Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO-I) Trial was a large trial evaluating thrombolytic therapy in patients with acute myocardial infarction. Patients with diabetes had approximately twice the 30-day mortality compared with patients without diabetes. In the evaluation of variables accounting for this increased mortality rate, diabetes remained after adjustment for all clinical and angiographic variables. This is an important finding and suggests that factors specific to diabetes as a metabolic disorder can affect immediate cardiac outcome after myocardial infarction. Although patients with diabetes presented with more coronary artery disease than patients without diabetes, the reasons accounting for this increased early mortality in diabetic patients are related to diabetes itself. <br /> Reference: <br /> Woodfield SL, Lundergan CF, Reiner JS, Greenhouse SW, Thompson MA, Rohrbeck SC, Deychak Y, Simoons ML, Califf RM, Topol EJ, Ross AM. Angiographic findings and outcome in diabetic patients treated with thrombolytic therapy for acute myocardial infarction: the GUSTO-I experience. J Am Coll Cardiol 1996;28:1661-1669. <br />
  • Overall 5-Year Mortality in the Bypass Angioplasty Revascularization Investigation (BARI-1) <br /> 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. <br /> Reference: <br /> 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;342:989-997. <br />
  • Impact of PTCA vs. CABG on Mortality in BARI-1 <br /> In the BARI Trial, there was no difference in the rate of myocardial infarction between patients randomized to PTCA and patients randomized to CABG in either the diabetic or nondiabetic group. In the absence of the occurrence of myocardial infarction in the follow-up period, surgery still provided a survival benefit in the diabetic group. In the nondiabetic group, there was no difference in survival free of myocardial infarction in the follow-up period whether the patients were randomized to PTCA or CABG. In those patients who did sustain a Q-wave myocardial infarction in the follow-up period, patients with diabetes who were randomized to PTCA had an alarming rate of early mortality after their myocardial infarction. In the other 3 groups of patients, there was no difference in outcome 5 years after the index myocardial infarction regardless of the treatment allocation. <br /> Reference: <br /> 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;342:989-997. <br />
  • Impact of Diabetes on 7-Year Survival in BARI <br /> At 7 years in BARI, there was a statistically significant survival advantage for patients randomized to CABG compared with PTCA (84.4% survival for CABG and 80.9% survival for PTCA). The observed differences in survival could be attributed to a substantial treatment difference in the survival of 353 patients with treated diabetes (76.4% for diabetics with CABG, 55.7% for diabetics with PTCA). Among the patients with diabetes, cumulative survival was nearly identical (86.4% for CABG, 86.8% for PTCA). <br /> Reference: <br /> BARI Investigators. Seven-year outcome in the Bypass Angioplasty Revascularization Investigation (BARI) by treatment and diabetic status. J Am Coll Cardiol 2000;35:1122-1129. <br />
  • Eight-Year Mortality in Emory Angioplasty vs Surgery Trial (EAST) <br /> The Emory Angioplasty versus Surgery Trial (EAST) has recently reported 8-year follow-up data on patients randomized to surgery versus PTCA. In the relatively small subset of patients with treated diabetes, 8-year survival favored surgery (75.5%) versus PTCA (60.1%), although the differences were not statistically significant (p=0.23). Patients without diabetes had virtually identical survival with either surgery or PTCA, similar to the results noted in BARI. <br /> Reference: <br /> King SB III, Kosinski AS, Guyton RA, Lembo NJ, Weintraub WS. Eight-year mortality in the Emory Angioplasty versus Surgery Trial. J Am Coll Cardiol 2000;35:1116-1121. <br />
  • 6-Month Angiographic Outcome after PTCA in Diabetes (377 Patients with 476 Lesions) <br /> In this study in consecutive patients with diabetes, angiography was performed at 6 months after PTCA to evaluate the presence of restenosis. Total occlusion was shown to be a manifestation of restenosis in patients with diabetes. In patients who had multivessel PTCA, as more sites underwent intervention, the risk for total occlusion as a manifestation of restenosis increased. Not only is the rate of restenosis higher in the diabetic patient, but asymptomatic total occlusion occurs much more commonly in these patients. <br /> Reference: <br /> Van Belle E, Abolmaali K, Bauters C, McFadden EP, Lablanche JM, Bertrand ME. Restenosis, late vessel occlusion and left ventricular function six months after balloon angioplasty in diabetic patients. J Am Coll Cardiol 1999;34:476-485. <br />
  • Impact of Restenosis and Total Occlusion on LV Function in Diabetes <br /> In patients with diabetes who do have total occlusion as a manifestation of restenosis, left ventricular ejection fraction generally falls. In the absence of total occlusion, whether or not restenosis has occurred, there is no change in left ventricular ejection fraction. This fall in ejection fraction may account for the poor prognosis overall in patients with diabetes mellitus once coronary artery disease has been diagnosed and treated. <br /> Reference: <br /> Van Belle E, Abolmaali K, Bauters C, McFadden EP, Lablanche JM, Bertrand ME. Restenosis, late vessel occlusion and left ventricular function six months after balloon angioplasty in diabetic patients. J Am Coll Cardiol 1999;34:476-485. <br />
  • Effect of Stents on Target Vessel Revascularization (TVR) after PTCA in Diabetes <br /> In this analysis of consecutive diabetic patients treated with PTCA in the 3-year period from April 1994 to June 1997, target vessel revascularization after PTCA was reduced with the wider utilization of stents. Stents prevent elastic recoil after PTCA and isolate late loss as the cause for restenosis. Although patients with diabetes have a higher restenosis rate, recent technological advances in angioplasty may improve outcome in patients with diabetes mellitus. <br /> Reference: <br /> Rankin JM, Buller CE, Al-Rashdan IR, Henderson MA, Hilton D, Hayden RI, Carere RG, Spinelli JJ. Coronary angioplasty in diabetics: have outcomes improved in the stent era? [abstract] Circulation 1998;98:I-79. <br /> <br />
  • Evaluation of Platelet IIb/IIIa Inhibitor for Stenting Trial (EPISTENT): Benefit of Abciximab and Stenting in Diabetes on Reducing TVR <br /> In addition to the widespread acceptance of coronary artery stenting based on reduced rates of revascularization, inhibition of platelet aggregation by blockade of the surface glycoprotein IIb/IIIa receptor has been shown to reduce the incidence of periprocedural complications in patients undergoing PTCA. The Evaluation of Platelet IIb/IIIa Inhibitor for Stenting Trial (EPISTENT) showed that among patients with diabetes, the combination of abciximab and stenting was associated with a lower rate of repeat target vessel revascularization at 6 months (8.1%), than was stenting and placebo (16.6%, p=0.02) or angioplasty and abciximab (18.4%, p=0.008). <br /> Reference: <br /> Lincoff AM, Califf RM, Moliterno DJ, Ellis SG, Ducas J, Kramer JH, Kleiman NS, Cohen EA, Booth JE, Sapp SK, Cabot CF, Topol EJ, for the Evaluation of Platelet IIb/IIIa Inhibition in Stenting Investigators. Complementary clinical benefits of coronary-artery stenting and blockade of platelet glycoprotein IIb/IIIa receptors. N Engl J Med 1999;341:319-327. <br />
  • EPISTENT: Optimization of PTCA/Stent Outcomes with Platelet IIb/IIa Inhibition <br /> The 6-month follow-up for EPISTENT also showed that abciximab therapy, irrespective of revascularization strategy (stent or balloon angioplasty) resulted in significant reductions in the 6-month death or myocardial infarction rate (6.2% for stent plus abciximab, 7.8% for balloon angioplasty plus abciximab, and 12.7% for stent plus placebo, p=0.029). <br /> Reference: <br /> Marso SP, Lincoff AM, Ellis SG, Bhatt DL, Tanguay JF, Kleiman NS, Hammoud T, Booth JE, Sapp SK, Topol EJ. Optimizing the percutaneous interventional outcomes for patients with diabetes mellitus: results of the EPISTENT (Evaluation of platelet IIb/IIIa inhibitor for stenting trial) diabetic substudy. Circulation 1999;100:2477-2484. <br />
  • Conclusions <br />
  • Future Directions <br />
  • Diabetic Dyslipidemia and Atherosclerosis <br />
  • Interrelation Between Atherosclerosis and Insulin Resistance <br /> Insulin resistance is associated with a panoply of abnormalities, including hypertension, hyperinsulinemia, hypertriglyceridemia with small, dense low-density lipoprotein (LDL) and low high-density lipoprotein (HDL), and hypercoagulability. Of course, insulin resistance is a major risk factor for the development of diabetes. Obesity plays a role both in exacerbating insulin resistance and as an independent risk factor for atherosclerosis. Therefore, any patient with insulin resistance has numerous reasons to be at very high risk for atherosclerosis. <br />
  • Insulin Resistance and Hyperinsulinemia: Clinical Clues <br /> Clues for the identification of hyperinsulinemic or insulin-resistant patients include abdominal obesity and the presence of hypertriglyceridemia and low HDL cholesterol. Glucose intolerance can sometimes be identified by the fasting glucose level, which may be between 100 and 125 mg/dL. Other characteristics of insulin-resistant individuals are hypertension and the presence of atherosclerotic cardiovascular disease. Also, certain ethnic groups, such as those from Southeast Asia and Native Americans, have very high genetic predispositions to develop insulin resistance. <br />
  • Dyslipidemia in the Insulin Resistance Syndrome <br /> Dyslipidemia in patients with the insulin resistance syndrome is characterized by an elevated level of total triglyceride, a reduced level of HDL cholesterol, and the presence of heterogeneity within LDL particles, with an increased proportion of LDL found as small, dense, cholesterol-poor particles. <br />
  • Dyslipidemias in Adults with Diabetes: Framingham Heart Study <br /> In an analysis from the Framingham Heart Study, lipid levels in men and women with and without diabetes were compared to levels in the overall U.S. population. For total cholesterol, LDL cholesterol, and triglycerides, the slide portrays the percentage of normal and diabetic men and normal and diabetic women who have values above the 90th percentile for those parameters, and for HDL cholesterol, the data show the proportion of normal and diabetic men and women in Framingham who are below the 10th percentile for the U.S. population. As you can see, for total cholesterol and LDL cholesterol, there were no differences between normal and diabetic men or between normal and diabetic women. However, the diabetic men and women had about twice the prevalence of low HDL cholesterol levels and about twice the prevalence of high triglyceride levels as did their nondiabetic counterparts. <br /> Reference: <br /> Garg A, Grundy SM. Management of dyslipidemia in NIDDM. Diabetes Care 1990;13:153-169. <br />
  • Mean Plasma Lipids at Diagnosis of Type 2 Diabetes—UKPDS <br /> In a comparison of diabetic men and women from the United Kingdom Prospective Diabetes Study (UKPDS) and normal healthy control subjects, total cholesterol levels did not differ between the diabetics and the control subjects. For LDL cholesterol, there was also no difference among the men; however, women with type 2 diabetes in UKPDS had slightly but significantly higher LDL cholesterol levels than their normal counterparts. The data are more striking, however, for both HDL cholesterol, which was lower in the diabetics for both genders, and for triglycerides, which were higher in the diabetic subjects than in the normal control subjects. <br /> Reference: <br /> U.K. Prospective Diabetes Study Group. U.K. Prospective Diabetes Study 27: plasma lipids and lipoproteins at diagnosis of NIDDM by age and sex. Diabetes Care 1997;20:1683-1687. <br />
  • Relation Between Insulin Resistance and Hypertriglyceridemia <br /> Data to support the relation between insulin resistance and diabetic dyslipidemia include the strong correlation between insulin response to an oral glucose challenge and plasma triglyceride levels, as found in this analysis of a large number of subjects studied many years ago at Stanford University. The r value of 0.73 indicates that about half the variability in plasma triglyceride levels in this group could be explained by variability in their insulin resistance as measured by insulin response to oral glucose. <br /> Reference: <br /> Olefsky JM, Farquhar JW, Reaven GM. Reappraisal of the role of insulin in hypertriglyceridemia. Am J Med 1974;57:551-560. <br />
  • Association Between Hyperinsulinemia and Low HDL-C <br /> In another study done at Stanford University, Reaven and colleagues found an association between hyperinsulinemia and low HDL cholesterol. In both nonobese and obese subjects, those who had insulin levels above the median had lower HDL cholesterol levels than did those with insulin levels below the median. <br /> Reference: <br /> Reaven GM. Insulin resistance and its consequences: non–insulin-dependent diabetes mellitus and coronary heart disease. In: LeRoith D, Taylor SI, Olefsky JM, eds. Diabetes Mellitus: a Fundamental and Clinical Text. Philadelphia: Lippincott-Raven, 1996:509-519. <br />
  • Mechanisms Relating Insulin Resistance and Dyslipidemia (I) <br /> The pathophysiologic basis for diabetic dyslipidemia and its relation to insulin resistance is presented over the next four slides. In the first, we see that insulin-resistant fat cells undergo greater breakdown of their stored triglycerides and greater release of free fatty acids into the circulation. This is a common abnormality seen in both obese and nonobese insulin-resistant subjects and those with type 2 diabetes. Increased fatty acids in the plasma leads to increased fatty acid uptake by the liver; in the fed state and in the presence of adequate glycogen stores, which is the common situation in patients with type 2 diabetes that is reasonably well controlled and certainly the case in the insulin-resistant nondiabetic subject, the liver takes those fatty acids and synthesizes them into triglycerides. <br />
  • Mechanisms Relating Insulin Resistance and Dyslipidemia (II) <br /> The presence of increased triglycerides stimulates the assembly and secretion of the apolipoprotein (apo) B and very low density lipoprotein. The result is an increased number of VLDL particles and increased level of triglycerides in the plasma, which leads to the rest of the diabetic dyslipidemic picture. <br />
  • Mechanisms Relating Insulin Resistance and Dyslipidemia (III) <br /> In the presence of increased VLDL in the plasma and normal levels of activity of the plasma protein cholesteryl ester transfer protein (CETP), VLDL triglycerides can be exchanged for HDL cholesterol. That is, a VLDL particle will give up a molecule of triglyceride, donating it to the HDL, in return for one of the cholesteryl ester molecules from HDL. This leads to two outcomes: a cholesterol-rich VLDL remnant particle that is atherogenic, and a triglyceride-rich cholesterol-depleted HDL particle. The triglyceride-rich HDL particle can undergo further modification including hydrolysis of its tryglyceride, probably by hepatic lipase, which leads to the dissociation of the structurally important protein apo A-I. The free apo A-I in plasma is cleared more rapidly than apo A-I associated with HDL particles. One of the sites of clearance is the kidney. In this situation, HDL cholesterol is reduced, and the amount of circulating apo A-I and therefore the number of HDL particles is also reduced. <br />
  • Mechanisms Relating Insulin Resistance and Dyslipidemia (IV) <br /> On the last slide in this series, we see a similar phenomena leading to small, dense LDL. Increased levels of VLDL triglyceride in the presence of CETP can promote the transfer of triglyceride into LDL in exchange for LDL cholesteryl ester. The triglyceride-rich LDL can undergo hydrolysis by hepatic lipase or lipoprotein lipase, which leads to a small, dense, cholesterol-depleted—and, in general, lipid-depleted—LDL particle. <br />
  • Dyslipidemia in Diabetes <br /> As described in the preceding slides, high triglyceride and high VLDL levels lead to low HDL, fewer HDL particles, and small, dense LDL. <br />
  • LDL Subclass Phenotypes in Diabetes Mellitus <br /> An increased proportion of LDL particles are small and dense—that is, characteristic of the intermediate and B phenotypes—in both diabetic men and diabetic women compared to their nondiabetic counterparts. <br /> References: <br /> Feingold KR, Grunfeld C, Pang M, Doerrler W, Krauss RM. LDL subclass phenotypes and triglyceride metabolism in non-insulin-dependent diabetes. Arterioscler Thromb 1992;12:1496-1502. <br /> Selby JV, Austin MA, Newman B, Zhang D, Quesenberry CP Jr, Mayer EJ, Krauss RM. LDL subclass phenotypes and the insulin resistance syndrome in women. Circulation 1993;88:381-387. <br />
  • Small, Dense LDL and CHD: Potential Atherogenic Mechanisms <br /> Data from in vitro and in vivo studies suggest that small, dense LDL may be particularly atherogenic. In vitro, small, dense LDL appears to be more susceptible to oxidative modification. Because they are smaller, these particles appear to penetrate the endothelial layer of the arterial wall more easily. The apo B molecule in small, dense LDL undergoes a conformational change that leads to decreased affinity for the LDL receptor, therefore allowing this LDL particle to remain in the circulation longer and be more liable to oxidative modification and uptake into the vessel wall. Finally, in population studies and small clinical studies, small, dense LDL is associated with the insulin-resistance syndrome as well as with high triglycerides and low HDL cholesterol. <br /> Reference: <br /> Austin MA, Edwards KL. Small, dense low density lipoproteins, the insulin resistance syndrome and noninsulin-dependent diabetes. Curr Opin Lipidol 1996;7:167-171. <br />
  • Hypertriglyceridemia and CHD Risk: Associated Abnormalities <br /> One should not focus extensively on the atherogenic potential of small, dense LDL to the exclusion of considering hypertriglyceridemia as a risk factor. There are a number of reasons to consider hypertriglyceridemia as at least a marker of increased atherogenic potential. First of all, hypertriglyceridemia is associated with the accumulation of chylomicron remnants, which we know can be atherogenic, and accumulation of VLDL remnants, which are also atherogenic. As previously discussed, hypertriglyceridemia generates small, dense LDL and is the basis for low HDL in the general population. Hypertriglyceridemia is also associated with increased coagulability and decreased fibrinolysis, as shown by its association with increased levels of plasminogen activator inhibitor 1 (PAI-1) and factor VII and its activation of prothrombin to thrombin. <br />
  • TG Metabolism in CHD: Studies in the Postprandial State <br /> An area that has not been adequately discussed is the abnormalities of triglyceride metabolism in the insulin-resistant diabetic population that occur not only when the patients are fasting, but also after they have eaten a fat-containing meal. Postprandial hypertriglyceridemia has been shown to be a marker for the presence of coronary heart disease. In a study conduced by Patsch and his colleagues several years ago, patients with documented coronary heart disease by angiography were compared with those with normal angiograms. In those with coronary heart disease, there was greater postprandial triglyceride excursion after ingestion of a fat meal. In other studies, this abnormality of postprandial lipemia has been found to be an independent predictor of the presence of atherosclerotic cardiovascular disease independent even of fasting triglyceride levels. <br /> Reference: <br /> Patsch JR, Miesenbock G, Hopferwieser T, Muhlberger V, Knapp E, Dunn JK, Gotto AM Jr, Patsch W. Relation of triglyceride metabolism and coronary artery disease: studies in the postprandial state. Arterioscler Thromb 1992;12:1336-1345. <br />
  • Factors Promoting Thromboembolic Disease in Diabetes <br /> Diabetes is associated with hypercoagulability and the predisposition for thromboembolic phenomena. Diabetics have increased fibrinogen, increased PAI-1 levels, and increased platelet aggregability; the latter is particularly a problem in the poorly controlled diabetic. <br /> Reference: <br /> Thompson SG, Kienast J, Pyke SD, Haverkate F, van de Loo JC, for the European Concerted Action on Thrombosis and Disabilities Angina Pectoris Study Group. Hemostatic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. N Engl J Med 1995;332:635-641. <br />
  • Adverse Effects on Balance Between Thrombosis and Fibrinolysis in Subjects with Diabetes <br /> Diabetic patients have an imbalance between thrombosis and fibrinolysis. The predisposition to thrombosis is reflected by platelet hyperaggregability, elevated levels of procoagulants, and decreased concentration and activity of antithrombotic factors. The predisposition to an attenuation of fibrinolysis is marked by decreased tissue plasminogen activator activity, increased PAI-1, and decreased concentrations of 2-antiplasmin. <br /> Reference: <br /> Sobel BE. Potentiation of vasculopathy by insulin: implications from an NHLBI clinical alert. Circulation 1996;93:1613-1615. <br />
  • PAI-1 Activity in Blood in Patients with Type 2 Diabetes <br /> Data from McGill et al. showed that PAI-1 activity is elevated in the blood of patients with type 2 diabetes, whether they are lean or obese. Obese subjects both with and without diabetes had much higher levels of PAI-1 than the nonobese subjects. PAI-1 levels are increased with hyperinsulinemia as well as with hypertriglyceridemia. <br /> Reference: <br /> McGill JB, Schneider DJ, Arfken CL, Lucore CL, Sobel BE. Factors responsible for impaired fibrinolysis in obese subjects and NIDDM patients. Diabetes 1994;43:104-109. <br />
  • Elevation of PAI-1 Induced by Hyperinsulinemia, Hyperglycemia, and Increased FFA in Blood of Normal Subjects <br /> Even in normal subjects, the induction of hyperinsulinemia and hyperglycemia along with increased free fatty acid levels, all of which were induced by an infusion of glucose and intralipid, resulted in a significant increase in plasma levels of PAI-1 over several hours. <br /> Reference: <br /> Calles-Escandon J, Mirza SA, Sobel BE, Schneider DJ. Induction of hyperinsulinemia combined with hyperglycemia and hypertriglyceridemia increases plasminogen activator inhibitor 1 in blood in normal human subjects. Diabetes 1998;47:290-293. <br />
  • Pharmacologic Agents for Treatment of Dyslipidemia <br /> In this slide, we can see a summary of the actions of the different classes of drugs available for treating the dyslipidemia of diabetes. The HMG-CoA reductase inhibitors, or statins, are very effective in lowering LDL cholesterol levels in patients with diabetes, have variable but often significant effects on triglyceride levels, and have a modest but potentially important ability to raise HDL cholesterol levels. The fibrates, of which gemfibrozil and fenofibrate are available in the United States, are very good at lowering triglycerides and raising HDL cholesterol levels. These effects of fibrates on triglycerides are usually better than those seen with statins. On the other hand, fibrates often have little effect on LDL cholesterol, and can even result in increased LDL levels in patients with more severe hypertriglyceridemia. Fenofibrate can lower LDL cholesterol significantly when used in patients with very high baseline LDL cholesterol levels. The bile acid–binding resins can achieve additional LDL cholesterol lowering when used with a statin, although GI side effects of the older resins may be particularly problematic in patients with diabetes. Newer, more potent bile acid sequestrants, such as colesevalem, may increase their efficacy in the diabetic population. Niacin is the best agent for raising HDL cholesterol and has significant effects on triglycerides and a modest ability to lower LDL cholesterol. Niacin appears to increase insulin resistance, however, and its use may require modification of the diabetic treatment regimen. <br /> Reference: <br /> American Diabetes Association. Management of dyslipidemia in adults with diabetes. Diabetes Care 2000;23(suppl 1):S57-S60. <br />
  • Order of Priorities for Treatment of Diabetic Dyslipidemia in Adults <br /> This slide presents the priorities for treating abnormalities of lipid metabolism set by the American Diabetes Association. LDL lowering is the first priority, based on the clinical trials showing marked reductions in morbidity when statins lower LDL cholesterol in the subgroups with diabetes. Raising HDL cholesterol is the second priority, followed by lowering triglycerides. ADA goals for all diabetics include an LDL cholesterol less than or equal to 100 mg/dL, an HDL cholesterol greater than 45 mg/dl (possibly even higher in women), and a triglyceride level less than 200 mg/dL. <br /> Reference: <br /> American Diabetes Association. Management of dyslipidemia in adults with diabetes. Diabetes Care 2000;23(suppl 1):S57-S60. <br />
  • Update on the metabolic syndrome <br />
  • Metabolic syndrome increases risk for CHD and type 2 diabetes <br /> The National Cholesterol Education Program (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. <br /> Reference: <br /> 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;285:2486-2497. <br />
  • High risk of impaired glucose tolerance and type 2 diabetes by OGTT in post-MI patients without known diabetes <br /> Recently, Norhammar et al. studied consecutive patients admitted to a Swedish coronary care unit who were confirmed to have had a mild coronary infarction. Subjects who were previously known to have diabetes were excluded from the study. An oral glucose tolerance test (OGTT) was given to the remaining 181 subjects. At discharge, 35% of these post-MI subjects had impaired glucose tolerance and 31% had newly discovered type 2 diabetes. Thus, about two thirds of post-MI patients not known previously to have diabetes have some form of glucose intolerance. Since glucose levels may rise in the peri-infarction period and the high rate of glucose intolerance could be an epiphenomenon, the authors repeated the OGTT 3 months later. At this time, 40% of the subjects had impaired glucose tolerance and 25% of the subjects had newly diagnosed diabetes. Thus, again about two thirds of the patients had some form of glucose intolerance. <br /> Reference: <br /> Norhammar A, Tenerz A, Nilsson G, et al. Glucose metabolism in patients with acute myocardial infarction and no previous diagnosis of diabetes mellitus: a prospective study. Lancet 2002;359:2140-2144. <br />
  • Increased metabolic syndrome in prediabetic subjects: baseline risk factors in subjects with normal glucose tolerance at baseline according to conversion status at 8-year follow-up: San Antonio Heart Study <br /> Baseline risk factors in subjects from the San Antonio Heart Study who had normal glucose tolerance at baseline are presented according to whether they developed type 2 diabetes 8 years later. The diagnosis of diabetes was based on oral glucose tolerance tests which were performed both at baseline and at the follow-up examination. Subjects who later developed type 2 diabetes had increased triglyceride level, decreased high-density lipoprotein cholesterol (HDL-C) level, increased systolic blood pressure (SBP), slightly increased fasting glucose level, and much higher insulin level than subjects who did not develop diabetes at their follow-up exam. These variables are all components of the metabolic syndrome as defined by either the NCEP or World Health Organization (WHO) criteria, suggesting a markedly increased incidence of the metabolic syndrome prior to the onset of type 2 diabetes. <br /> Reference: <br /> 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. <br />
  • Elevated risk of CVD prior to clinical diagnosis of type 2 diabetes: Nurses&apos; Health Study <br /> In the Nurses&apos; Health Study, the relationship of diabetes and cardiovascular disease (CVD) was examined in more than 100,000 female nurses followed up for 20 years. As expected, subjects who were not diabetic during the entire follow-up had the lowest rate of developing CVD. Subjects who had prevalent diabetes at the time of the baseline questionnaire had a 5-fold increased risk of CVD. Surprisingly, subject who developed CVD prior to the clinical onset of type 2 diabetes had a 2.8-fold increased risk of CVD relative to subjects who never developed diabetes. The group who developed CVD prior to the onset of type 2 diabetes could not be helped by intensive screening for type 2 diabetes. This study provides some of the strongest rationale for a strategy of diabetes prevention rather than simply screening for type 2 diabetes and CVD in high-risk populations. <br /> Reference: <br /> Hu FB, Stampfer MJ, Haffner SM, Solomon CG, Willett WC, Manson JE. Elevated risk of cardiovascular disease prior to clinical diagnosis of type 2 diabetes. Diabetes Care 2002;25:1129-1134. <br />
  • Risk of major CHD event associated with insulin quintiles in nondiabetic subjects: Helsinki Policemen Study <br /> The risk of developing fatal and nonfatal CHD in nondiabetic subjects was examined in the Helsinki Policemen Study. In 25-year follow-up, subjects with the highest insulin concentration had the greatest probability of developing CHD. <br /> Reference: <br /> Pyörälä M, Miettinen H, Laakso M, Pyorala K. Hyperinsulinemia predicts coronary heart disease risk in healthy middle-aged men: the 22-year follow-up results of the Helsinki Policemen Study. Circulation 1998;98:398-404. <br />
  • CVD risk factors across HOMA-IR quintiles: San Antonio Heart Study (Phase II) <br /> In cross-sectional data from the San Antonio Heart Study, homeostasis model assessment of insulin resistance (HOMA-IR) was very similar to fasting insulin in nondiabetic subjects (R=0.98). HOMA-IR = fasting insulin (pmol/l)  fasting insulin (U/ml) / 22.5. Higher levels of HOMA-IR were associated with higher triglyceride levels and higher levels of systolic and diastolic blood pressure as well as lower levels of HDL-C. As in other studies, HOMA-IR, a surrogate for insulin resistance, was not associated with LDL-C. <br /> Reference: <br /> Hanley AJ, Williams K, Stern MP, Haffner SM. Homeostasis model assessment of insulin resistance in relation to the incidence of cardiovascular disease: the San Antonio Heart Study. Diabetes Care 2002;25:1177-1184. <br />
  • Definitions of the metabolic syndrome <br /> The metabolic syndrome can be identified according to a variety of criteria. The NCEP criteria rely on readily accessible clinical criteria and assume that overweight and decreased physical activity are responsible for the majority of metabolic syndrome cases in western society. The WHO criteria emphasize the importance of insulin resistance as an underlying etiology for the metabolic syndrome and are relatively more friendly to pharmacological interventions. <br />
  • Definition of metabolic syndrome: according to underlying causes <br /> This slide shows three possible underlying causes for the metabolic syndrome. These underlying causes are not necessarily mutually exclusive, but different definitions of the metabolic syndrome place their emphasis on different variables. <br /> References: <br /> World Health Organization. Definition, Diagnosis and Classification of Diabetes Mellitus and Its Complications: Report of a WHO Consultation. Geneva: World Health Organization, 1999. <br /> 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;285:2486-2497. <br />
  • Therapeutic implications: according to underlying causes <br /> This slide shows the possible treatment implications for the different underlying causes of the metabolic syndrome. <br />
  • ATP III: the metabolic syndrome <br /> The NCEP ATP III guidelines define 5 components of the metabolic syndrome; at least 3 of the 5 criteria are required for the diagnosis of the metabolic syndrome. Note that the NCEP metabolic syndrome has different criteria for triglycerides and HDL-C, unlike the WHO definition, which lists high triglycerides and/or low HDL-C as a single factor. Almost all individuals in North America who have the metabolic syndrome have a high waist circumference as one of the criteria. Note also that the NCEP definition of the metabolic syndrome is more liberal than the NCEP major risk factors for blood pressure (140/90 mm Hg) and HDL-C (&lt;40 mg/dl in both men and women). <br /> Reference: <br /> 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;285:2486-2497. <br />
  • Prevalence of the NCEP metabolic syndrome: NHANES III by age <br /> This slide shows the prevalence of the metabolic syndrome as defined by NCEP in NHANES III participants by age. It is usually said that the prevalence of the metabolic syndrome in the United States is 23 or 24%. However, this is not a useful statement since the prevalence of the metabolic syndrome markedly increases with age. The prevalence of the metabolic syndrome is &lt;10% in individuals aged 20–29 years, 20% in individuals aged 40–49 years, and 45% in individuals aged 60–69 years. Thus it might be more useful to suggest that the estimated prevalence of the metabolic syndrome is an individual&apos;s age minus 20. <br /> Reference: <br /> Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. JAMA 2002;287:356-359. <br />
  • Prevalence of the NCEP metabolic syndrome: NHANES III by sex and race/ethnicity <br /> This slide shows the prevalence of the metabolic syndrome as defined by NCEP in NHANES III participants by sex and ethnicity. The prevalence of the metabolic syndrome is highest in Mexican American women and lowest in African American men. The prevalence of the metabolic syndrome (using the NCEP definition) is low in African Americans because African Americans have low triglycerides and high HDL-C levels and also because NCEP has separate criteria for triglycerides and HDL-C. Thus, the reports of the low prevalence of the metabolic syndrome in African Americans should be taken with caution since this ethnic group is known to have high rates of glucose intolerance and hypertension. <br /> Reference: <br /> Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. JAMA 2002;287:356-359. <br />
  • Prevalence of CHD by the metabolic syndrome and diabetes in the NHANES population age 50+ <br /> In an analysis of NHANES subjects age 50 or higher, about 85% of diabetic subjects had the metabolic syndrome. The 15% of diabetic subjects without the metabolic syndrome did not have a high prevalence of CHD. This is because almost all diabetic subjects in the United States are obese, and thus diabetic subjects without the metabolic syndrome have low triglyceride levels, high HDL-C levels, and blood pressure &lt;130/85 mm Hg without antihypertensive medicines. This appears to be a pretty unusual group of diabetic subjects. The subjects without diabetes and without the metabolic syndrome can of course have hypertension or lipid disorders. <br /> The most interesting feature in this analysis is the prevalence of CHD in subjects with the metabolic syndrome but without diabetes. In contrast to the previous work by Lakka et al., these subjects had a modestly increased prevalence of the metabolic syndrome (about 50–60% higher than subjects without diabetes and the metabolic syndrome). Thus, the presence of the metabolic syndrome without diabetes does not carry a CHD risk equivalent to that in subjects with CHD or diabetes. The precise degree of intensification for cardiovascular risk factor management in these subjects has not been defined. <br /> References: <br /> Alexander CM, Landsman PB, Teutsch SM, Haffner SM. NCEP-defined metabolic syndrome, diabetes, and prevalence of coronary heart disease among NHANES III participants age 50 years and older. Diabetes 2003;52:1210-1214. <br /> Lakka HM, Laaksonen DE, Lakka TA, Niskanen LK, Kumpusalo E, Tuomilehto J, Salonen JT. The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA 2002;288:2709-2716. <br />
  • ATP III metabolic syndrome: therapeutic implications <br /> The NCEP guidelines suggest a primary focus on treating the presumed behavioral causes of the metabolic syndrome. Thus the focus is principally on weight reduction and increased physical activity. The NCEP guidelines for treating the metabolic syndrome do state that risk factors for CHD such as lipid disorders and hypertension should be treated, and aspirin (if clinically indicated) should be used. NCEP does not state that conventional cardiovascular risk factor reduction should be intensified in subjects with the metabolic syndrome. NCEP also does not recommend the use of insulin sensitizers, such as thiazolidinediones (TZDs) or metformin, in nondiabetic subjects with the metabolic syndrome at the current time. <br /> References: <br /> 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;285:2486-2497. <br /> National Institutes of Health. National Heart, Lung, and Blood Institute in cooperation with National Institute of Diabetes and Digestive and Kidney Diseases. Obesity Education Initiative. Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults: the Evidence Report. NIH publication no. 98-4083. Bethesda, Md.: National Institutes of Health, 1998. <br />
  • Different components of the NCEP metabolic syndrome predict CHD: NHANES <br /> Although the metabolic syndrome predicts both type 2 diabetes and CHD, different components within the metabolic syndrome predict these two major outcomes of the metabolic syndrome. In this analysis of NHANES data, low HDL-C, blood pressure, and type 2 diabetes were associated with a high prevalence of CHD. Impaired fasting glucose, high triglycerides, and obesity were not associated with a high prevalence of CHD. When the individual components of the metabolic syndrome were included in a multiple logistic regression model, the metabolic syndrome did not add additional predictive power. The last observation has not universally been found in other reports. <br /> Reference: <br /> Alexander CM, Landsman PB, Teutsch SM, Haffner SM. NCEP-defined metabolic syndrome, diabetes, and prevalence of coronary heart disease among NHANES III participants age 50 years and older. Diabetes 2003;52:1210-1214. <br />
  • Different components of the NCEP metabolic syndrome predict diabetes: San Antonio Heart Study <br /> In the San Antonio Heart Study, obesity and fasting glucose were the strongest predictors of the development of type 2 diabetes, in contrast to the previous slide of predictors of CHD. Thus, it is difficult to answer the question &quot;which components of the metabolic syndrome are most important?&quot; without specifying the particular endpoints being studied. <br /> Reference: <br /> Stern MP, Williams K, Haffner SM. Identification of persons at high risk for type 2 diabetes mellitus: do we need the oral glucose tolerance test? Ann Intern Med 2002;136:575-581. <br />
  • WHO metabolic syndrome definition 1999: based on clinical criteria <br /> In the 1999 WHO definition of the metabolic syndrome, insulin resistance and/or impaired glucose tolerance is a required feature. Also, the WHO definition includes a number of variables not required by the simpler NCEP definition, namely a) oral glucose tolerance test, b) HOMA-IR, and c) urinary microalbuminuria. <br /> Reference: <br /> World Health Organization. Definition, Diagnosis and Classification of Diabetes Mellitus and Its Complications: Report of a WHO Consultation. Geneva: World Health Organization, 1999. <br />
  • Must insulin resistance be present for a patient to have the metabolic syndrome? <br /> The WHO definition requires subjects to have insulin resistance; however, the NCEP definition does not require insulin resistance, although most subjects who meet the NCEP definition are in fact insulin resistant. <br /> References: <br /> World Health Organization. Definition, Diagnosis and Classification of Diabetes Mellitus and Its Complications: Report of a WHO Consultation. Geneva: World Health Organization, 1999. <br /> 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;285:2486-2497. <br />
  • WHO metabolic syndrome definition 1999: therapeutic implications <br /> The WHO definition places more emphasis on insulin resistance as an underlying mechanism for the metabolic syndrome. Thus, one might focus on reducing obesity and increasing physical activity to improve insulin sensitivity as the NCEP definition requires. However, the WHO definition is also more friendly to the possible use of insulin-sensitizing intervention, particularly pharmacological intervention, in nondiabetic subjects. <br /> Reference: <br /> World Health Organization. Definition, Diagnosis and Classification of Diabetes Mellitus and Its Complications: Report of a WHO Consultation. Geneva: World Health Organization, 1999. <br />
  • Therapeutic implications of definition of metabolic syndrome <br /> The approach to the treatment of the metabolic syndrome is heavily dependent upon which concept of the metabolic syndrome is believed. If one believes that environmental factors such as obesity and decreased physical activity are the fundamental causes of the metabolic syndrome in most individuals in western society, as in the NCEP guidelines, then most of the efforts will be to reduce obesity and increase physical activity. If one believes that insulin resistance is the underlying cause of the metabolic syndrome, as in the WHO definition, then one might decrease insulin resistance either by behavioral measures or pharmacological interventions. If one believes that the major increase in cardiovascular risk is related to the underlying cardiovascular risk factors, as might be suggested by the NHANES analysis in slide 16, then one would focus mainly on the treatment of the underlying cardiovascular risk factors. <br />
  • Criteria for comparing different definitions for metabolic syndrome <br /> There are a number of criteria for assessing which definition of the metabolic syndrome might be superior. The first, obviously, is how strongly the definitions of the metabolic syndrome are related to the development of type 2 diabetes and CHD, but other important factors might include how closely the definitions are related to insulin resistance and how simple the definition is for use by practitioners in the community. <br />
  • Intensity of therapy should be proportionate to level of risk <br /> Several studies have suggested that the metabolic syndrome may be a risk factor for cardiovascular disease, although the strength of the association between the metabolic syndrome and cardiovascular disease varies widely among studies. Several national organizations suggest that the intensity of therapy should be dependent upon the degree of risk for a particular endpoint. For example, the ATP III guidelines suggest that the LDL-C goal should be lower in subjects with higher cardiovascular risk. Thus it is important that we have some estimate of the risk of the metabolic syndrome for cardiovascular disease and type 2 diabetes. Currently, the ATP III guidelines do not suggest intensification of cardiovascular risk factor management for subjects with the metabolic syndrome. <br />
  • Cardiovascular disease mortality increased in the metabolic syndrome: Kuopio Ischaemic Heart Disease Risk Factor Study <br /> In a study of slightly more than 1,000 males from Kuopio, Finland, followed up for 10 years, Lakka et al. showed a 3.5-fold increase in risk for cardiovascular disease mortality. This increased risk is as high as or higher than the risk of type 2 diabetes for cardiovascular disease in males described in many other studies such as the Framingham Study. Other studies such as the NHANES analysis in slide 16 suggest a much lower risk of the metabolic syndrome for cardiovascular disease in nondiabetic subjects. <br /> References: <br /> Lakka HM, Laaksonen DE, Lakka TA, Niskanen LK, Kumpusalo E, Tuomilehto J, Salonen JT. The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA 2002;288:2709-2716. <br /> Alexander CM, Landsman PB, Teutsch SM, Haffner SM. NCEP-defined metabolic syndrome, diabetes, and prevalence of coronary heart disease among NHANES III participants age 50 years and older. Diabetes 2003;52:1210-1214. <br />
  • Cox proportional hazard ratios (and 95% confidence intervals) predicting all-cause and cardiovascular mortality: San Antonio Heart Study 14-year follow-up <br /> In these data from the San Antonio Heart Study presented at the American Diabetes Association meeting in June 2003, the risk of the metabolic syndrome (as defined by NCEP) for cardiovascular disease in nondiabetic subjects was 2.0. Note that the WHO definition for the metabolic syndrome did not predict cardiovascular disease in the San Antonio Heart Study. <br /> Reference: <br /> Hunt KJ, Resendez RG, Williams K, Haffner SM, Stern MP. NCEP versus WHO metabolic syndrome in relation to all cause and cardiovascular mortality in the San Antonio Heart Study (SAHS) [abstract]. Diabetes 2003;52:A221-A222. <br />
  • Comparison of NCEP and 1999 WHO metabolic syndrome to identify insulin-resistant subjects: IRAS <br /> One way of assessing different definitions of the metabolic syndrome such as the NCEP and the 1999 WHO criteria is to assess how closely they are associated with insulin resistance. Dr. Hanley of the University of Toronto used the frequently sampled intravenous glucose tolerance test to determine insulin sensitivity (Si) and acute insulin response in nondiabetic subjects in the Insulin Resistance Atherosclerosis Study (IRAS). The WHO definition was better at identifying subjects in the lowest 25% of the Si distribution (most insulin resistant) than was the NCEP definition. Combining the NCEP and the WHO definitions identified the largest percentage of insulin-resistant subjects. <br /> Reference: <br /> Hanley AJ, Wagenknecht LE, D&apos;Agostino RB Jr, Zinman B, Haffner SM. Identification of subjects with insulin resistance and beta-cell dysfunction using alternative definitions of the metabolic syndrome. Diabetes 2003;52:2740-2747. <br />
  • CRP adds prognostic information at all levels of risk as defined by the Framingham risk score <br /> C-reactive protein (CRP), a marker of subclinical inflammation, has been examined prospectively for possible associations with the development of CHD, the metabolic syndrome, and type 2 diabetes. In this analysis from the Women&apos;s Health Study, both the Framingham Risk Score and CRP level independently predicted the risk for CHD. High CRP levels predicted the development of CHD in all global risk categories. Participants in the Women&apos;s Health Study are a population at very low risk for CHD; the overall risk for CHD was only 2% over 10 years of follow-up. Thus, high CRP levels in individuals with very low global risk may not mean that the individuals would have a high enough risk for CHD to require lipid therapy (usually defined as a 10-year risk for CHD of at least 10%). Therefore, CRP should mainly be used in intermediate-risk subjects, much as the American Heart Association and Centers for Disease Control and Prevention recommended in their guidelines published in Circulation in 2003. <br /> References: <br /> Ridker PM, Rifai N, Rose L, et al. Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med 2002;347:1557-1565. <br /> Pearson TA, Mensah GA, Alexander RW, et al. Markers of inflammation and cardiovascular disease: application to clinical and public health practice: a statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation 2003;107:499-511. <br />
  • Partial Spearman correlation analysis of inflammation markers with variables of IRS adjusted for age, sex, clinic, ethnicity, and smoking status: IRAS <br /> Increased subclinical inflammation as assessed by high levels of CRP has been associated with increased overall and centralized adiposity, increased fasting glucose and insulin concentration, and insulin resistance as determined by the frequently sampled intravenous glucose tolerance test. These data are from more than 1,000 nondiabetic subjects in the Insulin Resistance Atherosclerosis Study (IRAS). <br /> Reference: <br /> Festa A, D&apos;Agostino R Jr, Howard G, Mykkanen L, Tracy RP, Haffner SM. Chronic subclinical inflammation as part of the insulin resistance syndrome: the Insulin Resistance Atherosclerosis Study (IRAS). Circulation 2000;102:42-47. <br />
  • Mean values of CRP by number of metabolic disorders (dyslipidemia, upper body adiposity, insulin resistance, hypertension): IRAS <br /> As the number of metabolic disorders increased in nondiabetic subjects in IRAS, CRP levels increased in a monotonic fashion. This suggests that increased CRP levels are a feature of the metabolic syndrome. <br /> Reference: <br /> Festa A, D&apos;Agostino R Jr, Howard G, Mykkanen L, Tracy RP, Haffner SM. Chronic subclinical inflammation as part of the insulin resistance syndrome: the Insulin Resistance Atherosclerosis Study (IRAS). Circulation 2000;102:42-47. <br />
  • Five-year incidence of type 2 diabetes stratified by quartiles of inflammatory proteins: IRAS <br /> Increased levels of CRP and plasminogen activator inhibitor–1 (PAI-1) strongly predicted the incidence of type 2 diabetes in IRAS. <br /> Reference: <br /> Festa A, D&apos;Agostino R Jr, Tracy RP, Haffner SM. Elevated levels of acute-phase proteins and plasminogen activator inhibitor-1 predict the development of type 2 diabetes: the Insulin Resistance Atherosclerosis Study. Diabetes 2002;51:1131-1137. <br />
  • The effect of rosiglitazone on CRP <br /> In diabetic subjects, rosiglitazone, a thiazolidinedione (TZD), reduced levels of CRP by about 25%. Rosiglitazone is a diabetic agent that principally improves insulin resistance in the muscle. Therefore, this result provides additional information that subclinical inflammation is related to insulin resistance. <br /> Reference: <br /> Haffner SM, Greenberg AS, Weston WM, Chen H, Williams K, Freed MI. Effect of rosiglitazone treatment on nontraditional markers of cardiovascular disease in patients with type 2 diabetes mellitus. Circulation 2002;106:679-684. <br />
  • The effect of rosiglitazone on IL-6 <br /> However, rosiglitazone did not reduce concentrations of interleukin-6 (IL-6), a cytokine produced in adipocytes. This is puzzling because most investigators believe that the major stimulus to the production of CRP in the liver is from adipose tissue. Perhaps the measurement of IL-6 may not be sufficiently precise or other cytokines such as tumor necrosis factor– (TNF-) may be more important. <br /> Reference: <br /> Haffner SM, Greenberg AS, Weston WM, Chen H, Williams K, Freed MI. Effect of rosiglitazone treatment on nontraditional markers of cardiovascular disease in patients with type 2 diabetes mellitus. Circulation 2002;106:679-684. <br />
  • Reduction of CRP levels with statin therapy (n=22) <br /> As reported in a number of papers, statins decrease levels of CRP. In this case, pravastatin 40 mg, simvastatin 20 mg, or atorvastatin 10 mg each reduced CRP by 15–20%. <br /> Reference: <br /> Jialal I, Stein D, Balis D, Grundy SM, Adams-Huet B, Devaraj S. Effect of hydroxymethyl glutaryl coenzyme A reductase inhibitor therapy on high sensitive C-reactive protein levels. Circulation 2001;103:1933-1935. <br />
  • Summary of inflammation and the metabolic syndrome <br /> The metabolic syndrome and insulin resistance are associated with a proinflammatory state. CRP, which is higher in individuals with diabetes or characteristics of the metabolic syndrome, can be reduced by rosiglitazone, an insulin-sensitizing agent. <br />
  • Does lipid and blood pressure therapy work in subjects with the metabolic syndrome? <br /> Clinical trials have not been designed specifically to test the effect of lipid and blood pressure interventions in subjects with the metabolic syndrome. Diabetes may be considered as a good model of the metabolic syndrome, because 85% of diabetic subjects have the metabolic syndrome, and there are clear data that lipid and blood pressure interventions work very well in diabetic subjects. However, few data are currently available on the effectiveness of lipid and blood pressure intervention in nondiabetic subjects with the metabolic syndrome. <br />
  • CHD prevention trials with statins in diabetic subjects: subgroup analyses <br /> This slide compares the efficacy of statins in the general population and in the diabetic subset of several major clinical trials. In general, statins reduced the incidence of CHD as well in diabetic subjects as in nondiabetic subjects. AFCAPS/TexCAPS = Air Force/Texas Coronary Atherosclerosis Prevention Study; CARE = Cholesterol and Recurrent Events; HPS = Heart Protection Study; LIPID = Long-Term Intervention with Pravastatin in Ischaemic Disease; 4S = Scandinavian Simvastatin Survival Study. <br /> References: <br /> Downs JR, Clearfield M, Weis S, et al., for the AFCAPS/TexCAPS Research Group. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. JAMA 1998;279:1615-1622. <br /> Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet 2003;361:2005-2016. <br /> Goldberg RB, Mellies MJ, Sacks FM, et al. 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. <br /> Pyörälä K, Pedersen TR, Kjekshus J, et al., for the 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;20:614-620. <br /> Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med 1998;339:1349-1357. <br /> Haffner SM, Alexander CM, Cook TJ, et al., for the Scandinavian Simvastatin Survival Study Group. Reduced coronary events in simvastatin-treated patients with coronary heart disease and diabetes or impaired fasting glucose levels: subgroup analyses in the Scandinavian Simvastatin Survival Study. Arch Intern Med 1999;159:2661-2667. <br />
  • Completed clinical trials with antihypertensive agents in diabetes <br /> Blood pressure interventions have also been shown to markedly reduce CHD and stroke in diabetic subjects. SHEP = Systolic Hypertension in the Elderly Program; GISSI-3 = Gruppo Italiano per lo Studio della Sopravvivenza nell&apos;Infarto Miocardico–3; Syst-Eur = Systolic Hypertension in Europe; HOT = Hypertension Optimal Treatment; UKPDS = UK Prospective Diabetes Study; CAPPP = Captopril Prevention Project <br /> References: <br /> Curb JD, Pressel SL, Cutler JA, et al, for the Systolic Hypertension in the Elderly Program Cooperative Research Group. Effect of diuretic-based antihypertensive treatment on cardiovascular disease risk in older diabetic patients with isolated systolic hypertension. JAMA 1996;276:1886-1892. <br /> Zuanetti G, Latini R, Maggioni AP, et al. Effect of the ACE inhibitor lisinopril on mortality in diabetic patients with acute myocardial infarction: data from the GISSI-3 study. Circulation 1997;96:4239-4245. <br /> Staessen JA, Thijs L, Gasowski J, et al, for the Systolic Hypertension in Europe (Syst-Eur) Trial Investigators. Treatment of isolated systolic hypertension in the elderly: further evidence from the Systolic Hypertension in Europe (Syst-Eur) trial. Am J Cardiol 1998;82:20R-22R. <br /> Hansson L, Zanchetti A, Carruthers SG, et al, 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;351:1755-1762. <br /> UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ 1998;317:703-713. <br /> Hansson L, Lindholm LH, Niskanen L, et al, for the Captopril Prevention Project (CAPPP) Study Group. Effect of angiotensin-converting-enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: the Captopril Prevention Project (CAPPP) randomised trial. Lancet 1999;353:611-616. <br />
  • &quot;Metabolic syndrome&quot; in 4S <br /> This slide from the Scandinavian Simvastatin Survival Study (4S) suggests that simvastatin therapy if anything is more effective in subjects with the lipid triad (high LDL-C, high triglyceride, and low HDL-C levels), who are likely to have the metabolic syndrome, than in subjects with isolated high LDL-C levels. Note that the risk for CHD is much higher in placebo subjects with the lipid triad than in placebo subjects with isolated high LDL-C. <br /> Reference: <br /> Ballantyne CM, Olsson AG, Cook TJ, Mercuri MF, Pedersen TR, Kjekshus J, for the Scandinavian Simvastatin Survival Study (4S) Group. Influence of low high-density lipoprotein cholesterol and elevated triglyceride on coronary heart disease events and response to simvastatin therapy in 4S. Circulation 2001;104:3046-3051. <br />
  • Efficacy of multiple risk factor intervention in high-risk subjects (type 2 diabetes with microalbuminuria): Steno-2 <br /> The Steno-2 study showed the effect of a multiple risk factor intervention strategy in 160 subjects with type 2 diabetes with microalbuminuria. Although all these subjects had type 2 diabetes, the results suggest that multiple risk factor intervention may also be highly beneficial in subjects with the metabolic syndrome. Subjects in the intensive therapy group were to follow a reduced-fat diet and exercise regularly, offered smoking cessation counseling, prescribed an angiotensin-converting enzyme (ACE) inhibitor or angiotensin II–receptor blockers (ARB) regardless of blood pressure, and received vitamin supplementation and aspirin; stepwise antiglycemic and antihypertension medications were also prescribed as well as lipid-modifying therapy with a statin and/or fibrate. Subjects receiving intensive therapy were much more likely to reach their total cholesterol goal (&lt;175 mg/dl) and systolic blood pressure goal (&lt;130 mm Hg) and to routinely use angiotensin-converting enzyme (ACE) inhibitors or angiotensin II–receptor blockers (ARBs) (data not shown). Note that it was much more difficult to achieve systolic blood pressure goal than diastolic blood pressure goal. The difference between intensive and conventional therapy for hemoglobin A1c (glycosylated hemoglobin) was only 0.6%. <br /> Reference: <br /> Gæde 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;348:383-393. <br />
  • Composite endpoint of death from CV causes, nonfatal MI, CABG, PCI, nonfatal stroke, amputation, or surgery for PAD: STENO-2 <br /> In Steno-2, the intensive therapy group had a 53% reduction in macrovascular disease, relative to the conventional therapy group. This 53% reduction in macrovascular disease is much higher than the percent reduction reported in single intervention trials of blood pressure, lipids, or ACE inhibitors, suggesting that multiple risk factor interventions are critical in high-risk subjects. <br /> Reference: <br /> Gæde 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;348:383-393. <br />
  • Summary: metabolic syndrome <br /> Presence of the metabolic syndrome increases risk for diabetes and CHD. Most individuals with the metabolic syndrome have insulin resistance and obesity. Therapy should include caloric restriction and increased physical activity as well as treatment of established cardiovascular risk factors such as lipids and hypertension. <br />

Epidemiología de la Resistencia a la Insulina, Diabetes Mellitus y Enfermedad Coronaria Epidemiología de la Resistencia a la Insulina, Diabetes Mellitus y Enfermedad Coronaria Presentation Transcript

  • Epidemiology of Insulin Resistance, Diabetes Mellitus, and Coronary Heart Disease Steven Haffner, MD Slide Source LipidsOnline www.lipidsonline.org
  • Criteria for the Diagnosis of Diabetes Mellitus and Hyperglycemia Plasma Glucose Concentration Fasting Glucose Diabetes Mellitus 2-Hour Post Glucose Load >7.0 (>126) >11.1 (>200) Impaired Glucose Tolerance Impaired Fasting Glucose >7.8 (>140) to <11.1 (<200) >6.1 (>110) to <7.0 (<126) Values are mmol/L (mg/dl) Adapted from World Health Organization. Definition, Diagnosis and Classification of Diabetes Mellitus Slide Source and its Complications. Geneva: World Health Organization:1999:52. LipidsOnline www.lipidsonline.org
  • Percent Prevalence of Diabetes in Adult Population (Aged >20 years) by Year and Region 9 8 7 6 5 4 3 2 1 0 1995 Developed Developing King H et al. Diabetes Care 1998;21:1414-1431. 2000 2025 World Slide Source LipidsOnline www.lipidsonline.org
  • Hospitalization Costs for Chronic Complications of Diabetes in the US Ophthalmic disease Renal disease Others Neurologic disease Peripheral vascular disease  Total costs 12 billion US $  CVD accounts for 64% of total costs Cardiovascular disease American Diabetes Association. Economic Consequences of Diabetes Mellitus in the US in 1997. Alexandria, VA: American Diabetes Association, 1998:1-14. Slide Source LipidsOnline www.lipidsonline.org
  • Framingham Study: DM and CHD Mortality 20-Year Follow-up Annual CHD Deaths per 1000 Persons 18 16 14 17 17 DM Non-DM 12 10 8 8 6 4 4 2 0 Men Kannel WB, McGee DL. JAMA 1979;241:2035-2038. Women Slide Source LipidsOnline www.lipidsonline.org
  • Mortality in People with Diabetes Causes of Death 50 % of Deaths 40 30 20 10 0 Ischemic Other Diabetes Cancer heart heart disease disease Geiss LS et al. In: Diabetes in America. 2 nd Stroke Infection Other ed. 1995; chap 11. Slide Source LipidsOnline www.lipidsonline.org
  • Mortality Due to Heart Disease in Men and Women with or without Diabetes (US) Mortality per 1000 person-years* 35 30 29.9 Diabetes 19.2 20 15 10 11.5 11.0 7.1 6.3 3.6 5 0 No Diabetes 23.0 25 Men Women All heart disease Men Women Ischemic heart disease *Age-adjusted Adapted from Gu K et al. Diabetes Care 1998;21:1138-1145. Slide Source LipidsOnline www.lipidsonline.org
  • Rate per 1000 person-years Trends in Mortality Rates for Ischemic Heart Disease in NHANES Subjects with and without Diabetes* 20 15 Diabetes Nondiabetes 17.0 Men, cohort 1* Men, cohort 2** Women, cohort 1* Women, cohort 2** 14.2 10 6.8 7.6 7.4 4.2 5 2.4 1.9 0 -16.6% (P=0.46) +10.7% (P=0.76) -43.8% (P<0.001) *Defined in 1971-1975, followed up through 1982-1984. **Defined in 1982-1984, followed up through 1992-1993. Gu K et al. JAMA 1999;281:1291-1297. -20.4% (P=0.12) Slide Source LipidsOnline www.lipidsonline.org
  • Survival Post-MI in Diabetic and Nondiabetic Men and Women: Minnesota Heart Survey 100 MEN WOMEN 100 80 60 n=1628 Diabetes n=228 40 0 0 20 40 60 80 Months Post-MI No diabetes Survival (%) Survival (%) No diabetes 80 n=568 60 Diabetes 40 0 0 n=156 20 40 60 80 Months Post-MI Adapted from Sprafka JM et al. Diabetes Care 1991;14:537-543. Slide Source LipidsOnline www.lipidsonline.org
  • % of Deaths (Crude Rate) Cardiovascular Mortality in People with Diabetes MEN 60 50 40 WOMEN 28 d – 1 y Hospitalization – 28 d 9.1 15.4 30 4.2 9.6 20 10 0 28.6 Diabetes 22.1 No Diabetes 11.1 22.7 Out of Hospital 2.8 9.0 10.9 11.9 Diabetes No Diabetes Adapted from Miettinen H et al. Diabetes Care. 1998;21:69-75. Slide Source LipidsOnline www.lipidsonline.org
  • Age-adjusted CVD death rate per 10,000 person-years Influence of Multiple Risk Factors* on CVD Death Rates in Diabetic and Nondiabetic Men: MRFIT Screenees 140 120 No diabetes Diabetes 100 80 60 40 20 0 None One only Two only *Serum cholesterol >200 mg/dl, smoking, SBP >120 mmHg Stamler J et al. Diabetes Care 1993;16:434-444 All three Slide Source LipidsOnline www.lipidsonline.org
  • Putative Mechanism for Increased Atherosclerosis in Type 2 Diabetes BLACK BOX  Dyslipidemia  Hypertension  Hyperinsulinemia/insulin resistance  Hemostatic abnormalities  Hyperglycemia  AGE proteins  Oxidative stress AGE = advanced glycation end products Adapted from Bierman EL. Arterioscler Thromb 1992;12:647-656. Slide Source LipidsOnline www.lipidsonline.org
  • Prevalence of Cardiovascular Risk Factors in Diabetic Subjects Relative to Nondiabetics Risk Factor Dyslipidemia Hypertriglyceridemia Low HDL Small, dense LDL Increased apo B Hypertension Hyperinsulinemia/insulin resistance Central obesity Family history of atherosclerosis Cigarette smoking Type 1 Type 2 + – – – + – – – – ++ ++ ++ ++ ++ ++ ++ + – + = moderately increased compared with nondiabetic population ++ = markedly increased compared with nondiabetic population – = not different compared with nondiabetic population Adapted from Chait A, Bierman EL. In: Joslin’s Diabetes Mellitus. Philadelphia: Lea & Febiger, Slide Source LipidsOnline 1994:648-664. www.lipidsonline.org
  • Differences in HDL Cholesterol and LDL Size by Diabetic Status in Women and Men Differences between participants with and without diabetes HDL Cholesterol mg/dL 0 LDL Size Å 0 -2 -2 -4 -4 -6 Women -6 Men -8 Women Men -8 Howard BV et al. Diabetes Care 1998; 21:1258-1265. Slide Source LipidsOnline www.lipidsonline.org
  • Strategies for Reduction of Diabetic Complications  Microvascular complications - Aggressive screening - Improved metabolic control  Macrovascular complications - Improved glycemic control (positive but minor) - Prevention of type 2 diabetes - Aggressive treatment of established CVRF in diabetic and possibly prediabetic subjects - Diabetic agents that improve cardiovascular risk Slide Source LipidsOnline www.lipidsonline.org
  • 50 40 Years (%) Incidence per 1000 Person Incidence Rates of MI and Microvascular Endpoints by Mean Systolic Blood Pressure: UKPDS Myocardial Infarction 30 20 10 0 110 Microvascular Endpoints 120 130 140 150 160 170 Updated Mean Systolic Blood Pressure (mmHg) Adjusted for age, sex, and ethnic group Adler AI et al. BMJ 2000;321:412-419. Slide Source LipidsOnline www.lipidsonline.org
  • Incidence per 1000 Person Years (%) Incidence Rates of MI and Microvascular Endpoints by Mean Hemoglobin A1c: UKPDS 80 60 Myocardial Infarction 40 20 Microvascular Endpoints 0 5 6 7 8 9 10 11 Updated Mean Hemoglobin A1c Concentration (%) Adjusted for age, sex, and ethnic group Stratton IM et al. BMJ 2000;321:405-412. Slide Source LipidsOnline www.lipidsonline.org
  • Plasma Insulin and Triglycerides Predict Ischemic Heart Disease: Quebec Cardiovascular Study 6.7 Odds Ratio 8.0 5.4 6.0 P=0.002 p=0.005 4.0 1.5 2.0 0.0 4.6 P<0.001 p=0.001 5.3 1.0 <12 Triglycerides >150 mg/dl <150 mg/dl 12-15 F-Insulin (µU/ml) Despres JP et al. N Engl J Med 1996;334:952-957. >15 Slide Source LipidsOnline www.lipidsonline.org
  • Plasma Insulin and Apolipoprotein B Predict Ischemic Heart Disease: Quebec Cardiovascular Study 12.0 9.7 p<0.001 10.0 Odds Ratio 11.0 P<0.001 8.0 6.0 Apolipoprotein B 4.0 2.0 0.0 1.5 1.0 <12 3.0 3.2 p=0.04 p=0.04 12-15 >15 F-Insulin (µU/ml) Despres JP et al. N Engl J Med 1996;334:952-957. >119 mg/dl <119 mg/dl Slide Source LipidsOnline www.lipidsonline.org
  • LDL Particle Size and Apolipoprotein B Predict Ischemic Heart Disease: Quebec Cardiovascular Study 6 6.2 5 (p<0.001) 4 3 2.0 2 1 0 1.0 Apo B 1.0 >120 mg/dl <120 mg/dl >25.64 <25.64 LDL Peak Particle Diameter (nm) Lamarche B et al. Circulation 1997;95:69-75. Slide Source LipidsOnline www.lipidsonline.org
  • Baseline Anthropometric Variables and Cardiovascular Risk Factors in Subjects with Normal Glucose Tolerance at Baseline According to Conversion Status at 8-Year Followup: San Antonio Heart Study Conversion Status at Follow-up Diabetes (n=18) Normal (n=490) P 28.2 + 1.1 27.2 + 0.2 .472 Centrality* 1.38 + 0.09 1.16 + 0.2 .472 TG (mmol) 1.83 + 0.12 1.26 + 0.10 .006 HDLC (mmol) 1.14 + 0.07 1.28 + 0.02 .045 SBP (mmHg) 116.8 + 3.0 108.8 + 0.8 .004 5.28 + 0.1 5.00 + 0.02 .032 157 + 27 81 + 5 .006 BMI (kg/m2) Fasting glucose (mmol) Fasting insulin (pmol) * Ratio of subscapular to triceps skinfolds Haffner SM et al. JAMA 1990;263:2893-2898. Slide Source LipidsOnline www.lipidsonline.org
  • “Ticking Clock” Hypothesis For The “clock starts ticking” Microvascular complications At onset of hyperglycemia Macrovascular complications Before the diagnosis of hyperglycemia WHO. Diabetologia 1985;28:615-640; Haffner SM et al. JAMA 1990;263:2893-2898. Slide Source LipidsOnline www.lipidsonline.org
  • The 7-Year Age-Adjusted Incidence of CHD Mortality and All CHD Events: East-West Study 30 CHD Mortality All CHD Events 20 10 0 40 % Incidence % Incidence 40 Fasting Glucose <9.6 9.6-13.4 >13.4 P-glucose (mmol/L) Lehto S et al. Diabetes 1997;46:1354-1359. 30 Hemoglobin A1 CHD Mortality All CHD Events 20 10 0 <8.9 8.9-10.7 >10.7 HbA1 (%) Source Slide LipidsOnline www.lipidsonline.org
  • Stepwise Selection of Risk Factors* in 2693 White Patients with Type 2 Diabetes with Dependent Variable as Time to First Event: UKPDS Coronary Artery Disease (n=280) Position in Model Variable P Value First Low-Density Lipoprotein Cholesterol <0.0001 Second High-Density Lipoprotein Cholesterol 0.0001 Third Hemoglobin A1c 0.0022 Fourth Fifth Systolic Blood Pressure Smoking *Adjusted for age and sex. Turner RC et al. BMJ 1998;316:823-828. 0.0065 0.056 Slide Source LipidsOnline www.lipidsonline.org
  • Criteria for Accepting Cardiovascular Risk Factor Management as Similar in Diabetic and CHD Subjects  The risk of vascular disease is similar in diabetic subjects without pre-existing vascular disease as in nondiabetic subjects with vascular disease  Glycemia alone will not completely eliminate the excess of CHD risk in diabetic subjects  Lipid interventions to reduce CHD can be equally effective in diabetic and nondiabetic subjects Slide Source LipidsOnline www.lipidsonline.org
  • 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 Incidence During Follow-up (%) 50 40 30 20 Nondiabetics with prior MI Nondiabetics with no prior MI p<0.001 Diabetics with prior MI Diabetics with no prior MI 20.2 18.8 10 0 45.0 (n=69) Events per 100 person-yr: 3.0 P<0.001 3.5 (n=1304) 0.5 Haffner SM et al. N Engl J Med 1998;339:229-234. (n=169) 7.8 (n=890) 3.2 Slide Source LipidsOnline www.lipidsonline.org
  • Incidence of Fatal or Nonfatal Stroke During a 7-Year Follow-up in Relation to History of MI in Nondiabetic vs Diabetic Subjects: East-West Study Incidence During Follow-up (%) 25 20 15 10 Nondiabetics with prior MI Nondiabetics with no prior MI p<0.001 Diabetics with prior MI Diabetics with no prior MI 10.3 7.2 5 0 19.5 (n=69) Events per 100 person-yr: 1.2 P=0.01 1.9 (n=1304) 0.3 Haffner SM et al. N Engl J Med 1998;339:229-234. (n=169) 3.4 (n=890) 1.6 Slide Source LipidsOnline www.lipidsonline.org
  • Conclusions  Epidemiological data suggest that the risk of CHD in type 2 diabetes is equivalent to that in people with prevalent CHD.  Although hyperglycemia is significantly related to CHD, the magnitude of association is unlikely to explain the entire excess risk of cardiovascular disease.  Within type 2 diabetics, increased blood pressure and LDL-C and low HDL-C also predict the risk of future myocardial infarction. Slide Source LipidsOnline www.lipidsonline.org
  • Clinical Trials and Guidelines for Lipid Management in the Diabetic Patient Steven Haffner, MD Slide Source LipidsOnline www.lipidsonline.org
  • UKPDS Design Aim  To determine whether intensified blood glucose control, with either sulphonylurea or insulin, reduces the risk of macrovascular or microvascular complications in type 2 diabetes Patients  3867 newly diagnosed type 2 diabetic patients who were asymptomatic after 3 months of diet; fasting glucose 6.1-15 mmol/L (110-270 mg/dl); treat for 10 years Adapted from UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:837-853; Slide Source LipidsOnline Turner R et al. Ann Intern Med 1996;124:136-145. www.lipidsonline.org
  • UKPDS 10-Year Follow-up Results: Glycemic Control, Weight, and Plasma Insulin Conventional 9 8 Intensive 7 6 0 7.5 Weight Intensive 5 2.5 0 -2.5 Conventional Baseline = 75 kg 0 1 2 3 4 5 6 7 8 9 10 11 12 Years from Randomization UKPDS Group. Lancet 1998;352:837-853. Median (%) 10 9 Fasting plasma glucose Median Change (pmol/L) Mean Change (kg) Median (mmol/L) 11 Hemoglobin A1c 8 Conventional Intensive 7 6 0 40 30 Plasma insulin 20 Intensive 10 0 -10 -20 Baseline = 89 pmol/L 0 1 2 3 4 5 6 Conventional 7 8 9 10 11 12 Years from Randomization Slide Source LipidsOnline www.lipidsonline.org
  • UKPDS: Proportion of Patients Taking Different Therapies in the Conventional-Therapy Group 100 Additional pharmacologic therapy % of patients 80 60 40 Diet alone 20 1 Courtesy of Dr. Amanda Adler 3 5 7 9 11 Years from randomization Slide Source LipidsOnline www.lipidsonline.org
  • UKPDS: Causes of Death by Glucose Treatment Group Cause MI Stroke Sudden death PVD Intensive Rate/1000 patient-years % Conventional Rate/1000 patient-years % 7.6 1.6 0.9 0.1 43 9 5 1 8.0 1.3 1.6 0.3 43 7 8 2 10.2 58 11.2 60 Renal disease 0.3 2 0.2 1 Cancer Other specified Unknown 4.4 2.4 0.5 25 13 3 4.4 2.7 0.2 24 14 1 17.8 100 18.7 100 All macrovascular Total UKPDS Group. Lancet 1998;352:837-853. Slide Source LipidsOnline www.lipidsonline.org
  • UKPDS: Endpoints by Glucose Treatment Group Intensive Cause Conventional Rate/1000 Rate/1000 Patient-Years Patient-Years P % Risk Reduction Any diabetes-related* 40.9 46.0 0.029 12 MI 14.7 17.4 0.052 16 Stroke 5.6 5.0 0.52 – PVD** 1.1 1.6 0.15 – Microvascular 8.6 11.4 0.0099 25 *Combined microvascular and macrovascular events **Amputation or death from PVD UKPDS Group. Lancet 1998;352:837-853. Slide Source LipidsOnline www.lipidsonline.org
  • UKPDS: Impact of Glucose-Lowering Agents on MI and Stroke  Sulphonylurea or exogenous insulin (n=2729) MI 16% reduction (P = 0.052) Stroke 11% increase (P = 0.52)  Metformin in overweight subjects (n = 342) MI 39% reduction (P = 0.01) Stroke 41% reduction (P = 0.13) Adapted from UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:837-853; Slide Source UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:854-865. LipidsOnline www.lipidsonline.org
  • UKPDS Results: Intensive Blood Pressure Control Intensive Blood Pressure Control Reduction (%) P Value Any diabetes-related endpoint 24 0.0046 Deaths related to diabetes 32 0.019 Myocardial infarction 21 NS Stroke 44 0.013 Microvascular disease 37 0.092 Adapted from UK Prospective Diabetes Study Group. BMJ 1998;317:703-713. Slide Source LipidsOnline www.lipidsonline.org
  • Comparison of Captopril vs. Atenolol in UKPDS RR for Captopril P Value Any diabetes-related endpoint 1.10 (0.86–1.41) 0.43 Death related to diabetes 1.27 (0.82–1.97) 0.28 All-cause mortality 1.14 (0.81–1.61) 0.44 Myocardial infarction 1.20 (0.82–1.76) 0.35 Stroke 1.12 (0.59–2.12) 0.74 Peripheral vascular disease 1.48 (0.35–6.19) 0.59 Microvascular disease 1.29 (0.80–2.10) 0.30 Clinical Endpoint  Primary  Secondary Adapted from UK Prospective Diabetes Study Group. BMJ 1998;317:713-720. Slide Source LipidsOnline www.lipidsonline.org
  • Comparison of Glucose Lowering and Blood Pressure Lowering in UKPDS Intensive Blood Intensive Blood Glucose Control (n=2729) Pressure Control (n=758) Reduction % P Value Reduction % P Value Any diabetes-related endpoint 12 0.029 24 0.0046 Myocardial infarction 16 0.052 21 NS 11↑ NS 44 0.013 25 0.0099 37 0.092 Stroke Microvascular disease ↑ = Increase in risk Adapted from UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:837-853; Slide Source UK Prospective Diabetes Study Group. BMJ 1998;317:703-713. LipidsOnline www.lipidsonline.org
  • Treatment Strategies for Diabetic Dyslipidemia  Primary Strategy - Lower LDL cholesterol  Secondary Strategy - Raise HDL cholesterol - Lower triglycerides  Other Approaches - Non-HDL cholesterol - ApoB - Remnants Adapted from American Diabetes Association. Diabetes Care. 2000;23(suppl 1):S57-S60; Chait A, Brunzell JD. Diabetes Mellitus. A Fundamental and Clinical Text. Philadelphia: Lippincott Raven, 1996;772-779; Source Slide LipidsOnline European Diabetes Policy Group 1999. Diabet Med. 1999;16:716-730. www.lipidsonline.org
  • CHD Prevention Trials with Statins in Diabetic Subjects: Subgroup Analyses Study Drug No. Baseline LDL-C, mg/dl (mmol/L) LDL-C Lowering Primary Prevention AFCAPS/TexCAPS Lovastatin 239 150 (3.9) 25% CARE Pravastatin 586 136 (3.6) 28% 4S Simvastatin 202 186 (4.8) 36% LIPID Pravastatin 782 150* (3.9) 25%* Secondary Prevention *Values for overall group Adapted from Downs JR et al. JAMA 1998;279:1615-1622; Goldberg RB et al. Circulation 1998;98:2513-2519; Pyörälä K et al. Diabetes Care 1997;20:614-620; Haffner SM et al. Arch Intern Med 1999;159:2661-2667; The Long-Term Slide Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. N Engl J Med 1998;339:1349-1357. Source LipidsOnline www.lipidsonline.org
  • CHD Prevention Trials with Statins in Diabetic Subjects: Subgroup Analyses (cont’d) Study Drug CHD Risk Reduction No. (overall) CHD Risk Reduction (diabetes) Primary Prevention AFCAPS/TexCAPS Lovastatin 239 37% 43% CARE Pravastatin 586 23% 25% (p=0.05) 4S Simvastatin 202 32% 55% (p=0.002) LIPID Pravastatin 782 25% 19% 4S-Extended Simvastatin 483 32% 42% (p=0.001) Secondary Prevention Adapted from Downs JR et al. JAMA 1998;279:1615-1622; Goldberg RB et al. Circulation 1998;98:2513-2519; Pyörälä K et al. Diabetes Care 1997;20:614-620; The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. N Engl J Med 1998;339:1349-1357; Haffner SM et al. Arch Intern Med 1999;159:2661-2667. Slide Source LipidsOnline www.lipidsonline.org
  • Diabetic vs. Nondiabetic Patients in 4S Placebo Better Simvastatin Better P=0.001 P=0.087 Total mortality CHD mortality P<0.0001 P=0.242 Major CHD event P<0.0001 P=0.002 Cerebrovascular event P=0.097 P=0.071 Any atherosclerotic event P<0.0001 P=0.018 0 No diabetes Diabetes 0.2 0.4 0.6 0.8 1.0 1.2 1.4 Relative Risk with 95% Confidence Intervals Reduced Adapted from Pyörälä et al. Diabetes Care 1997;20:614-620. Increased Slide Source LipidsOnline www.lipidsonline.org
  • Major Coronary Events in 4S Patients with or without Diabetes by History (n=202) Proportion without Major CHD Event 1.0 0.9 0.8 0.7 0.6 Diabetes by Hx, simvastatin Diabetes by Hx, placebo 0.5 No diabetes by Hx, simvastatin No diabetes by Hx, placebo 0 0 1 P=0.002 P=0.0001 2 3 4 5 Years Since Randomization Adapted from Pyörälä et al. Diabetes Care 1997;20:614-620. 6 Slide Source LipidsOnline www.lipidsonline.org
  • 4S: Extended Diabetic Subgroup Analysis: Diabetes (n=483; 251 on Simvastatin) — Fasting Glucose >7 mmol/L (126 mg/dl) 0.72 CHD mortality (P=0.26) 0.79 Total mortality (P=0.34) 0.52 Revascularizations (P=0.005) 0.58 Major coronary events (P=0.001) 0.0 0.2 0.4 0.6 0.8 1.0 Relative Risk Adapted from Haffner SM et al. Arch Intern Med 1999;159:2661-2667 1.2 1.4 Slide Source LipidsOnline www.lipidsonline.org
  • 4S: Extended Diabetic Subgroup Analysis: Impaired Fasting Glucose (n=678; 343 on Simvastatin) — Fasting Glucose 6.0-6.9 mmol/L (110-125 mg/dl) 0.45 CHD mortality (P=0.007) 0.57 Total mortality (P=0.02) 0.57 Revascularizations (P=0.01) 0.62 Major coronary events (P=0.003) 0.0 0.2 0.4 0.6 0.8 1.0 Relative Risk Adapted from Haffner SM et al. Arch Intern Med 1999;159:2661-2667 1.2 1.4 Slide Source LipidsOnline www.lipidsonline.org
  • 4S: Effect of Statin Therapy on Hospital Stay Bed Days (per 100 Pts) 1200 ↓ 55% 1000 800 600 (p<0.001) ↓ 28% (p<0.001) ↓ 38% (p=0.005) 400 200 0 Simvastatin Placebo Normal fasting glucose Simvastatin Placebo Simvastatin Impaired fasting glucose Adapted from Herman WH et al. Diabetes Care 1999;22:1771-1778. Placebo Diabetes mellitus Slide Source LipidsOnline www.lipidsonline.org
  • CARE: Major Coronary Events in Diabetic Subgroups Relative risk = 0.77 P<0.001 35 30 25 Placebo 20 15 10 Pravastatin 5 0 0 1 2 3 4 5 6 Follow-up Time (years) 45 Percent with Event Percent with Event 45 No Diabetes by History 35 30 25 Diabetes by History Relative risk = 0.75 P=0.05 Placebo 20 Pravastatin 15 10 5 0 0 1 2 3 4 5 6 Follow-up Time (years) Adapted from Goldberg RB et al. Circulation 1998;98:2513-2519. Slide Source LipidsOnline www.lipidsonline.org
  • AFCAPS/TexCAPS: Subgroup Analysis 0 Men Women Older Smokers HTN Diabetes % Risk Reduction -10 -20 -30 -40 -50 -31 -37 -38 -46 -60 -70 -42 -58 Lovastatin Reduced the Risk of Acute MCE Downs JR et al. JAMA 1998;279:1615-1622. Slide Source LipidsOnline www.lipidsonline.org
  • 45 40 35 30 25 20 15 10 5 0 No Diabetes by History Relative risk = 0.77 P<0.001 Placebo Pravastatin 0 1 2 3 4 5 6 Follow-up Time (years) Percent with Event Percent with Event CARE: Major Coronary Events in Diabetic Subgroups 45 40 35 30 25 20 15 10 5 0 Diabetes by History Relative risk = 0.75 P=0.05 Placebo Pravastatin 0 1 2 3 4 5 6 Follow-up Time (years) Adapted from Goldberg RB et al. Circulation 1998;98:2513-2519. Slide Source LipidsOnline www.lipidsonline.org
  • Per-Patient % of Grafts POST-CABG: Effect of Aggressive Lipid Lowering on Progression in a Diabetic Subgroup 50 Diabetes (n=116) No Diabetes (n=1235) 40 30 51%  40%  20 10 0 99% CI (0.20-1.19) Aggressive Moderate Rx Rx Hoogwerf BJ et al. Diabetes. 1999;48:1289-1294. 99% CI (0.46-0.79) Aggressive Moderate Rx Rx Slide Source LipidsOnline www.lipidsonline.org
  • CHD Prevention Trials with Fibrates in Diabetic Subjects: Subgroup Analyses Drug Dose Study Baseline LDL-C, mg/dl No. (mmol/L) LDL-C CHD Lowering Reduction Primary Prevention Helsinki Heart Study Gemfibrozil 135 (1200 mg/d) 203 (5.2) 6% 68% NS 112 (2.9) – 24% p=0.05 Secondary Prevention VA-HIT Gemfibrozil 627 (1200 mg/d) Adapted from Koskinen P et al. Diabetes Care 1992;15:820-825; Rubins HB et al. N Engl J Med 1999;341:410-418. Slide Source LipidsOnline www.lipidsonline.org
  • 5-Year Incidence of CHD (%) Primary CHD* Prevention in Type 2 Diabetic Patients: The Helsinki Heart Study 15 P=0.19 10.5 P<0.02 10 7.4 5 0 3.4 3.3 Type 2 (n=135) Others (n=3946) Type 2 on Placebo (n=76) *Myocardial infarction or cardiac death Adapted from Koskinen P et al. Diabetes Care 1992;15:820-825. Type 2 on Gemfibrozil (n=59) Slide Source LipidsOnline www.lipidsonline.org
  • Cumulative Incidence (%) VA-HIT: Incidence of Death from CHD and Nonfatal MI 25 20 Placebo 15 Gemfibrozil 10 5 0 1 2 3 Year 4 Adapted from Rubins HB et al. N Engl J Med 1999;341:410-418. 5 6 Slide Source LipidsOnline www.lipidsonline.org
  • VA-HIT: Death Due to CHD, Nonfatal MI, and Confirmed Stroke in Diabetic Patients Placebo* 88/309 24% 0.05 (28) 214/949 170/955 24% 0.009 (23) No diabetes 116/318 (36) Diabetes Gemfibrozil* Risk Reduction (18) *Values are numbers with events/total numbers (%) Adapted from Rubins HB et al. N Engl J Med 1999;341:410-418. P Value Slide Source LipidsOnline www.lipidsonline.org
  • Future Directions Ongoing Trials with Lipid-Lowering Focus Drug HPS Simvastatin ASPEN Atorvastatin CARDS Atorvastatin LDS Cerivastatin + fenofibrate micronized DAIS Fenofibrate micronized FIELD Fenofibrate micronized HPS = Heart Protection Study; ASPEN = Atorvastatin Study in Preventing Endpoints in NIDDM; CARDS = Collaborative Atorvastatin Diabetes Study; LDS = Lipids in Diabetes Study; DAIS = Diabetes Atherosclerosis Intervention Study; FIELD = Fenofibrate Intervention Slide Source and Event Lowering in Diabetes LipidsOnline www.lipidsonline.org
  • Heart Protection Study  Primary prevention with risk factors (hypertension, diabetes, and CVA)  2x2 factorial design simvastatin 40 mg/day, antioxidant cocktail (600 mg vitamin E, 250 mg vitamin C, 20 mg beta carotene)  N = 20,000; subgroups include: Women (n ~ 5,000) Elderly (>65, n ~ 10,000) Diabetics (n ~ 6,000) Stroke (n ~ 3,000) Hypertension (n ~ 8,000) Noncoronary vascular disease (n ~ 7,000) Low to average blood cholesterol (n ~ 8,000)  FPI – 1996, fully enrolled, results 2001 Medical Research Council. August 1994 Slide Source LipidsOnline www.lipidsonline.org
  • Endpoint Studies: Treating to New Targets (TNT): Study Design Atorvastatin 80 mg 10,000 CAD Patients LDL 75 mg/dL 5 Years Atorvastatin LDL 10 mg 100 mg/dL Site Selection November 1997 Investigator Meeting March 1998 Recruitment Complete June 1999 Study End Dec 2004 Slide Source LipidsOnline www.lipidsonline.org
  • Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine with Simvastatin and Folic Acid/Vitamin B12 (SEARCH): Study Design  Primary objective: To determine whether the greater cholesterol reductions achieved with simvastatin 80 mg produce greater CHD reductions in post-MI patients than achieved with simvastatin 20 mg  Secondary prevention  2x2 factorial design: simvastatin 20 or 80 mg; 2 mg folic acid/1 mg Vitamin B12  N = 12,000  FPI – 12/97, results 2003 Slide Source LipidsOnline www.lipidsonline.org
  • Lipids in Diabetes Study (LDS): Two-by-Two Factorial Randomization Fenofibrate Arm Cerivastatin Arm Cerivastatin Fenofibrate (n=1,250) Placebo Fenofibrate (n=1,250) 2,500 active fenofibrate Cerivastatin Placebo (n=1,250) Placebo Placebo (n=1,250) 2,500 placebo fenofibrate n=2,500 active cerivastatin n=2,500 placebo cerivastatin 5,000 pts in total Slide Source LipidsOnline www.lipidsonline.org
  • Conclusions  CHD risk is extremely high in diabetic subjects  Benefits of risk-factor modification in intervention trials also apply to subgroups with diabetes  Results of strict glycemic control on macrovascular disease are inconclusive Slide Source LipidsOnline www.lipidsonline.org
  • Clinical Evaluation and Nonlipid Treatment of Coronary Artery Disease in the Diabetic Patient Richard Nesto, MD Slide Source LipidsOnline www.lipidsonline.org
  • Prevalence of Asymptomatic CAD in Diabetes Mellitus Positive Positive ETT Koistinen MJ. BMJ 1990;301:92-95. Type 2 Type 1 Controls Angiography n = 64 n = 72 n = 80 36% 24% 9% 9% 11% 9% n = 142 n = 149 31% 30% 12.1% 5.3% n = 925 12.1% Naka M et al. Am Heart J 1992;123:46-53. Type 2 Controls MiSAD Group. Am J Cardiol 1997;79:134-139. Type 2 6.4% (thal201) Rutter MK et al. Am J Cardiol 1999;83:27-31. Type 2 w microalb Type 2 w/o microalb n = 43 n = 43 65% 40% — — Le A et al. Am J Kidney Dis 1994;24:65-71. Type 1 Renal Transplant 58% 35% 55% 43% Holley JL et al. Am J Med 1991;90:563-570. Type 1 & 2 Renal Transplant Slide Source LipidsOnline www.lipidsonline.org
  • Indications for Cardiac Testing in Diabetic Patients  Typical or atypical cardiac symptoms  Resting ECG suggestive of ischemia or infarction  Peripheral or carotid occlusive arterial disease  Sedentary lifestyle or plan to begin a vigorous exercise program  Two or more of the risk factors listed below - Total cholesterol >240 mg/dL, LDL cholesterol >160 mg/dL, or HDL cholesterol <35 mg/dL - Blood pressure >140/90 mmHg - Smoking - Family history of premature CAD - Positive micro/macroalbuminuria Slide Source LipidsOnline www.lipidsonline.org
  • Factors Limiting Accuracy of Noninvasive "Stress" Tests for CAD  Hypertensive Cardiomyopathy  Diabetic Cardiomyopathy  Autonomic Cardiomyopathy  Renal Insufficiency  Microvascular Dysfunction Slide Source LipidsOnline www.lipidsonline.org
  • Benefits of Early Detection of CAD  Implement more aggressive CHD prevention regimen  Initiate anti-ischemic medications  Identify patients who would benefit from revascularization  Educate patients to recognize coronary symptoms Slide Source LipidsOnline www.lipidsonline.org
  • MEN 180 No Glucose Intolerance 160 140 174 Glucose Intolerance 120 119 100 90 80 77 60 40 20 0 59 50 38 24 105 135 165 Age-adjusted CV Event Rate/1,000 Age-adjusted CV Event Rate/1,000 Blood Pressure and CVD: Framingham Heart Study WOMEN 180 No Glucose Intolerance 160 140 Glucose Intolerance 120 113 100 80 74 60 40 20 195 Systolic BP (mmHg) Kannel WB et al. Am Heart J 1991;121:1268-1273. 0 56 48 31 15 105 36 23 135 165 195 Systolic BP (mmHg) Slide Source LipidsOnline www.lipidsonline.org
  • Effect of Glycemic Control in the UK Prospective Diabetes Study (UKPDS) Endpoints Intensive (rate/1000 pt yrs) Conventional (rate/1000 pt yrs) P % Decrease Any diabetes related* 40.9 46 0.029 11 MI 17.4 0.052 16 14.7 Stroke 5.6 5 0.52 – PVD 1.1 1.6 0.15 – Microvascular 8.6 11.4 0.0099 25 * Combined microvascular and macrovascular events UKPDS Group. Lancet 1998;352:837-853. Slide Source LipidsOnline www.lipidsonline.org
  • Reasons for Death in UKPDS Intensive Treatment Arm: 10-Year Follow-up N= 2729 (%) Fatal MI or SD 231 (8.4%) Cancer 120 (4.4%) Other 74 (2.9%) Fatal Stroke 43 (1.6%) Renal Disease 16 (0.6%) Accidents 5 (0.2%) PVD 2 (0.07%) Hypo- or Hyperglycemia 1 (0.04%) Accidents, PVD, Hypo& Hyperglycemia Renal 3.3% 2.5% 15% Other 24% Cancer 47% MI or SD 8.7% Stroke UKPDS Group. Lancet 1998;352:837-853. Slide Source LipidsOnline www.lipidsonline.org
  • Effect of Blood Pressure Control in the UKPDS Tight vs. Less Tight Control  1,148 Type 2 patients  Average BP lowered to 144/82 mmHg (controls: 154/87); 9-year follow-up Tight Control Risk Reduction (%) P value Any diabetes-related endpoint 24 0.0046 Diabetes-related deaths 32 0.019 Heart failure 56 0.0043 Stroke 44 0.013 Myocardial infarction 21 NS Microvascular disease 37 0.0092 UKPDS Group. BMJ 1998;317:703-713. Slide Source LipidsOnline www.lipidsonline.org
  • UKPDS: ACE Inhibitor vs. Beta-blocker for HTN Aggregate Clinical Endpoints Relative Risk & 95% CI RR p Any diabetes-related endpoint 1.10 1.27 1.14 0.44 Myocardial infarction 1.20 0.35 Stroke 1.12 0.74 Microvascular 1.29 2 0.28 All-cause mortality 1 0.43 Diabetes-related deaths 0.5 0.30 Favors ACE inhibitor UKPDS Group. BMJ 1998;317:713-720. Favors Beta blocker Slide Source LipidsOnline www.lipidsonline.org
  • Systolic Hypertension in Europe (Syst-Eur) Trial: Events / 1000 Pt-Years Effect of Systolic BP Control on All Cardiovascular Events at 2 Years 70 60 50 40 30 20 10 0 57.6 25% 62% Risk Reduction 22.0 Placebo Active Rx Diabetic Patients N=492; P=0.002 Tuomilehto J et al. NEJM 1999;340: 677-684. 31.4 Risk Reduction 23.5 Placebo Active Rx Nondiabetic Patients N=4,203; P=0.02 Slide Source LipidsOnline www.lipidsonline.org
  • Major Outcomes of the Hypertension Optimal Treatment (HOT) Trial: Diabetes Subgroup Events / 1000 Pt-Years 30 25 Diastolic Target p<0.005 <90 mmHg (N=501) <85 mmHg (N=501) 20 <80 mmHg (N=499) 15 p<0.045 10 p<0.016 5 0 Major CV Events Hansson L et al. Lancet 1998;351: 1755-1762. MI CV Mortality Slide Source LipidsOnline www.lipidsonline.org
  • Events / 1000 Pt-Years HOT Trial:Cardiovascular Events in Diabetics and Nondiabetics—Effect of Diastolic Target at 4 Years 30 25 20 15 10 24.4 48% Risk 18.6 Reduction 11.9 5 0 <90 <85 <80 Diabetic Patients n=1,501; p=0.016 Hansson L et al. Lancet 1998;351: 1755-1762. 9.9 10.0 9.3 <90 <85 <80 Nondiabetic Patients n=18,790; p=NS Slide Source LipidsOnline www.lipidsonline.org
  • Completed Clinical Trials with Antihypertensive Agents in Diabetes Trial Diabetic/Total SHEP 583/4736 Beneficial GISSI-3 2790/18,131 Beneficial Syst-Eur 492/4695 Beneficial 1501/18,790 Beneficial UKPDS 1148 Beneficial CAPPP 572/10,985 Beneficial HOT Results on CVD SHEP = Systolic Hypertension in the Elderly Program; GISSI = Grupo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico; Syst-Eur = Systolic Hypertension in Europe; HOT = Hypertension Optimal Treatment; CAPPP = Captopril Prevention Project Curb JD et al. JAMA 1996;276:1886-1892; Zuanetti G et al. Circulation 1997;96:4239-4245; Staessen JA et al. Am J Cardiol 1998;82:20R-22R; Hansson L et al. Lancet 1998;351:1755-1762;UK Prospective Diabetes Study Slide Source Group. BMJ 1998;317:703-713; Hansson L et al. Lancet 1999;353:611-616. LipidsOnline www.lipidsonline.org
  • Heart Outcomes Prevention Evaluation (HOPE) Study Effect of Ramipril on Cardiovascular Events (Myocardial Infarction, Stroke, or CVD Death) ~ 4.5 Yrs % of Patients 25 20 15 24% 19.8 Risk Reduction 15.0 10 21% 16.4 Risk Reduction 13.0 5 0 Placebo Ramipril Diabetic Patients N=3,578, P=<0.001 Hope Study Investigators. NEJM 2000;342:145-153. Placebo Ramipril Nondiabetic Patients N=5,719, P=<0.001 Slide Source LipidsOnline www.lipidsonline.org
  • Diabetes Increases Risk of Coronary Plaque Disruption and Thrombosis Cause of Myocardial Infarction Platelet Aggregation F VII Fibrinogen F VIII vWF Coronary Artery Thrombus Plaque Formation Plaque Disruption Sympathetic Tone PAI-1 TPA PGI2 Slide Source LipidsOnline www.lipidsonline.org
  • Impact of Serum Fibrinogen and Total Cholesterol Levels on Risk of Coronary Events in ECAT 21/305 16/304 7 6 Risk of Coronary Events (%) 3/247 5 4 3 2 5/311 10/281 9/261 4/306 11/266 10/282 1 Total Cholesterol Higher Middle 0 Lower Middle Fibrinogen Thompson SG. N Engl J Med 1995;332:635-641. Lower Higher Slide Source LipidsOnline www.lipidsonline.org
  • Effect of Aspirin on Mortality in Type 2 Patients with CHD: Bezafibrate Infarction Prevention Study 100 Survival (%) OR=0.7 (0.6-0.8) No diabetes 90 OR=0.8 (0.7-0.9) 80 Type 2 diabetes No aspirin Aspirin 70 0 1 2 3 4 Time (Years) Harpaz D et al. Am J Med 1998;105:494-499. 5 6 Slide Source LipidsOnline www.lipidsonline.org
  • Antiplatelet Agents Reduce CVD Events in Patients with Diabetes: Antiplatelet Trialists’ Collaboration CVD Events (%) 25 P<0.002 Antiplatelet Therapy Control 20 P<0.00001 15 10 5 0 Diabetes Antiplatelet Trialists’ Collaboration. BMJ 1994;308:81-106. No Diabetes Slide Source LipidsOnline www.lipidsonline.org
  • Diabetes Mellitus Insulin Glucose Infusion in Acute Myocardial Infarction (DIGAMI): Benefit of Tight Glycemic Control in No Insulin – Low Risk Cohort Total Cohort p = .0111 Mortality 0.6 0.7 0.5 Control 0.4 n=306 0.3 0.2 0 0 1 2 3 4 Years in Study 0.5 n=133 0.4 Control 0.3 0.2 Insulin-glucose Infusion 0.1 p = .004 0.6 n=314 Mortality 0.7 No Insulin – Low Risk n=139 0.1 5 Malmberg K et al. BMJ 1997;314:1512-1515. 0 0 Insulin-glucose Infusion 1 2 3 4 Years in Study Slide Source LipidsOnline www.lipidsonline.org 5
  • Effect of Trandolapril on Post-MI CHF Progression: Trandolapril Cardiac Evaluation (TRACE) Diabetics (n=237) 0.5 0.5 Placebo 0.4 Event Rate Event Rate 0.4 0.3 Trandolapril 0.2 0.1 0.0 Nondiabetics (n=1512) 1 2 Years 3 Placebo 0.2 Trandolapril 0.1 Relative risk, 0.38 P<0.001 0 0.3 4 0.0 Gustafsson I et al. J Am Coll Cardiol 1999;34:83-89. Relative risk, 0.81 P = 0.1 0 1 2 Years 3 Slide Source LipidsOnline www.lipidsonline.org 4
  • Effect of Trandolapril on Secondary Endpoints in TRACE Diabetics End Point RR (95% CI) Interaction Nondiabetics P RR (95% CI) P P Cardiovascular death 0.56 (0.37-0.85) 0.01 0.79 (0.66-0.96) 0.02 0.17 Sudden death 0.46 (0.25-0.85) 0.01 0.84 (0.63-1.12) 0.23 0.09 Reinfarction 0.55 (0.29-1.07) 0.08 0.93 (0.69-1.26) 0.65 0.15 Progression in CHF 0.38 (0.21-0.67) <0.001 0.81 (0.63-1.04) 0.10 0.03 CI = confidence interval; RR = relative risk. Gustafsson I et al. J Am Coll Cardiol 1999;34:83-89. Slide Source LipidsOnline www.lipidsonline.org
  • Effect of Diabetes on 30-Day Mortality: Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO-I) 2.7 Diabetes vs no diabetes (unadjusted) 2.1 Adjusted for clinical variables 2.4 Adjusted for angiographic variables 2.0 Adjusted for clinical & angiographic variables 0 1 2 3 4 Odds Ratio for 30-Day Mortality Woodfield SL et al. J Am Coll Cardiol 1996;28:1661-1669. Slide Source LipidsOnline www.lipidsonline.org 5
  • Overall 5-Year Mortality in the Bypass Angioplasty Revascularization Investigation (BARI-1) 1.0 DM-PTCA Mortality 0.8 DM-CABG Non DM-CABG 0.6 Non DM-PTCA 0.4 0.25 0.18 0.08 0.07 0.2 0.0 0 1 2 3 Follow-up (years) Detre KM et al. N Engl J Med 2000;342:989-997. 4 5 Slide Source LipidsOnline www.lipidsonline.org
  • Impact of PTCA vs. CABG on Mortality in BARI-1 Mortality in Patients without Q-MI 1.0 DM-CABG 0.8 Non DM-CABG Non DM-PTCA 0.6 Mortality Mortality 1.0 DM-PTCA 0.8 0.4 0.2 0.0 0 1 2 3 4 Follow-up (years) Mortality in Patients After Q-MI 0.79 0.6 0.4 0.22 0.2 0.16 0.07 0.06 0.0 5 Detre KM et al. N Engl J Med 2000;342:989-997. 0.29 0.27 0.17 0 1 2 3 4 Years after Q-MI 5 Slide Source LipidsOnline www.lipidsonline.org
  • Impact of Diabetes on 7-year Survival in BARI All Patients 84.4 80.9 80 60 40 CABG (n=914) PTCA (n=915) 20 0 1 2 3 Patients with Treated Diabetes 100 % Survival 0 76.4 60 55.7 CABG (n=180) PTCA (n=173) 20 0 0 1 2 3 4 p = 0.0011 4 5 6 5 6 7 80 86.8 86.4 60 40 CABG (n=734) PTCA (n=742) 20 0 Years 7 Patients without Treated Diabetes 100 80 40 p = 0.0425 % Survival % Survival 100 0 BARI Investigators. J Am Coll Cardiol 2000;35:1122-1129. 1 2 3 p = 0.7155 4 5 Source 7 Slide 6 LipidsOnline www.lipidsonline.org
  • Eight-Year Mortality in Emory Angioplasty vs Surgery Trial (EAST) All EAST Patients % Survival 100 80 60 40 CABG (n=194) PTCA (n=198) 20 0 0 1 2 4 5 60 40 CABG (n=30) PTCA (n=29) 20 p = 0.23 6 100 % Survival 80 0 3 p = 0.40 Treated Diabetic Patients 100 % Survival 82.7 79.3 7 8 Patients without Diabetes 80 60 40 20 CABG (n=164) PTCA (n=169) 0 7 8 0 1 2 Years after Randomization King SB III et al. J Am Coll Cardiol 2000;35:1116-1121. 0 1 2 3 4 5 6 3 4 p = 0.71 5 6 7 Slide Source LipidsOnline www.lipidsonline.org 8
  • 6-Month Angiographic Outcome after PTCA in Diabetes (377 Patients with 476 Lesions) Lesions (%) 75 62% 50 49% 25 0 Restenosis (n = 237) Total Occlusion (n = 60) 13% 100 Total Occlusion 75 Patients (%) 100 Overall Restenosis Rate 50 37% 25% 25 11% 0 Angiographic FU = 6 months Van Belle E et al. J Am Coll Cardiol 1999;34:476-485. 1 Site 2 Sites 3 Sites PTCA Site(s) Slide Source LipidsOnline www.lipidsonline.org
  • Impact of Restenosis and Total Occlusion on LV Function in Diabetes 15 Restenosis (–) Restenosis (+) Total Occlusion (+) Total Occlusion (–) Total Occlusion (–) (n = 297) (n = 237) (n = 60) ∆ in EF (%) 10 5 0 -5 -1.5+9.5 +0.5+9.9 -6.2+9.9 -10 -15 -20 p = ns p = ns Van Belle E et al. J Am Coll Cardiol 1999;34:476-485. p = 0.0001 Slide Source LipidsOnline www.lipidsonline.org
  • Effect of Stents on Target Vessel Revascularization (TVR) after PTCA in Diabetes Proportion Free of TVR 1.00 p = 0.021 df = 3, Log-rank Test 0.95 0.90 0.85 1997 0.80 Year 0 17.4 425 24.9 1996 480 41.0 1997 0 305 1995 0.70 % Stent 1994 0.75 N 288 55.5 2 1996 1995 1994 4 6 8 10 12 Months Post PTCA Rankin JM et al. Circulation 1998;98:I-79. Slide Source LipidsOnline www.lipidsonline.org
  • Patients with Diabetes (n = 491) 20 Stent + Placebo Stent + Abciximab Angioplasty + Abciximab 15 16.6% 10 8.1% 5 0 18.4% 0 30 60 90 120 150 180 Incidence of repeated TVR at 6 mos. (%) Incidence of repeated TVR at 6 mos. (%) Evaluation of Platelet IIb/IIIa Inhibitor for Stenting Trial (EPISTENT): Benefit of Abciximab and Stenting in Diabetes on Reducing TVR Days after Randomization Lincoff AM et al. N Engl J Med 1999;341:319-327. Patients without Diabetes (n = 1908) 20 Stent + Placebo Stent + Abciximab Angioplasty + Abciximab 15 9.0% 10 8.8% 5 0 14.6% 0 30 60 90 120 150 180 Days after Randomization Slide Source LipidsOnline www.lipidsonline.org
  • EPISTENT: Optimization of PTCA/Stent Outcomes with Platelet IIb/IIIa Inhibition 6-Month Death, MI for Diabetics 15 % of Patients 12.7% p = 0.029 10 7.8% 6.2% 5 0 Stent + Placebo Stent + Abciximab PTCA + Abciximab 0 30 60 90 Days Marso SP et al. Circulation 1999;100:2477-2484. 120 150 180 Slide Source LipidsOnline www.lipidsonline.org
  • Conclusions In patients with diabetes mellitus, there are numerous opportunities to reduce morbidity and mortality from CAD:  identify diabetic patients with particularly high risk for CAD and perform appropriate screening  aggressively identify and modify coronary risk factors  explore and implement treatment to protect the left ventricle from ischemic injury  maintain tight but judicious glycemic control in acute coronary syndromes  use medications proven to dramatically improve outcomes in acute MI (beta blockers, ACE inhibitors, aspirin, IIb/IIIa platelet inhibitors, statins) Slide Source LipidsOnline www.lipidsonline.org
  • Future Directions  Additional clinical trials are needed to evaluate cardiovascular therapeutic interventions in diabetic patients, because certain therapies may produce different results in the presence of diabetes Slide Source LipidsOnline www.lipidsonline.org
  • Diabetic Dyslipidemia and Atherosclerosis Henry Ginsberg, MD Slide Source LipidsOnline www.lipidsonline.org
  • Interrelation Between Atherosclerosis and Insulin Resistance Hypertension Obesity Hyperinsulinemia Insulin Insulin Resistance Resistance Diabetes Hypertriglyceridemia Atherosclerosis Atherosclerosis Small, dense LDL Low HDL Hypercoagulability Slide Source LipidsOnline www.lipidsonline.org
  • Insulin Resistance and Hyperinsulinemia: Clinical Clues  Abdominal obesity   TG +  HDL-C  Glucose intolerance  Hypertension  Atherosclerosis  Ethnicity Slide Source LipidsOnline www.lipidsonline.org
  • Dyslipidemia in the Insulin Resistance Syndrome  Elevated total TG  Reduced HDL-C  Small, dense LDL-C Slide Source LipidsOnline www.lipidsonline.org
  • Dyslipidemias in Adults with Diabetes Framingham Heart Study MEN WOMEN Normal DM Normal DM Increased cholesterol 14% 13% 21% 24% Increased LDL 11% 9% 16% 15% Decreased HDL 12% 21% 10% 25% 9% 19% 8% 17% Increased triglycerides Garg A et al. Diabetes Care 1990;13:153-169. Slide Source LipidsOnline www.lipidsonline.org
  • Mean Plasma Lipids at Diagnosis of Type 2 Diabetes - UKPDS MEN Type 2 WOMEN Control Type 2 Control 2139 52 1574 143 TC (mg/dl) 213 205 224 217 LDL-C (mg/dl) 139 132 151* 135 43 43* 55 103 159* 95 Number of Pts HDL-C (mg/dl) TG (mg/dl) 39** 159* * P<0.001, ** P<0.02 comparing type 2 vs. controll UKPDS Group. Diabetes Care 1997;20:1683-1687. Slide Source LipidsOnline www.lipidsonline.org
  • Relation Between Insulin Resistance and Hypertriglyceridemia Plasma TG (mg/dL) 625 500 r = 0.73 P < 0.0001 400 300 200 100 100 200 300 400 500 600 Insulin Response to Oral Glucose* * Total area under 3-hour response curve (mean of 2 tests). Olefsky JM et al. Am J Med. 1974;57:551-560. Slide Source LipidsOnline www.lipidsonline.org
  • Association Between Hyperinsulinemia and Low HDL-C HDL-C (mg/dL) 60 50 Hyperinsulinemic P<0.005 Normoinsulinemic P<0.005 40 30 20 Nonobese Reaven GM. In: LeRoith D et al., eds. Diabetes Mellitus. Philadelphia: Lippincott-Raven,1996:509-519. Obese Slide Source LipidsOnline www.lipidsonline.org
  • Mechanisms Relating Insulin Resistance and Dyslipidemia Fat Cells Liver  FFA IR X Insulin Slide Source LipidsOnline www.lipidsonline.org
  • Mechanisms Relating Insulin Resistance and Dyslipidemia Fat Cells Liver  FFA IR X    TG Apo B VLDL VLDL Insulin Slide Source LipidsOnline www.lipidsonline.org
  • Mechanisms Relating Insulin Resistance and Dyslipidemia Fat Cells Liver  FFA IR X Insulin    CE TG Apo B VLDL  VLDL (CETP) HDL TG (hepatic lipase) Apo A-1 Kidney Slide Source LipidsOnline www.lipidsonline.org
  • Mechanisms Relating Insulin Resistance and Dyslipidemia Fat Cells Liver  FFA IR X    CE TG Apo B VLDL  VLDL (hepatic (CETP) HDL lipase) TG Apo A-1 CE (CETP) TG Insulin LDL Kidney SD LDL (lipoprotein or hepatic lipase) Slide Source LipidsOnline www.lipidsonline.org
  • Dyslipidemia in Diabetes Increased Decreased  Triglycerides  HDL  VLDL  Apo A-I  LDL and small dense LDL  Apo B Slide Source LipidsOnline www.lipidsonline.org
  • LDL Subclass Phenotypes in Diabetes Mellitus LDL Subclass n A Int B 51 24 36 6 Men* Diabetic Nondiabetic 29 87 28 47 Percent 21 29 Women** Diabetic Nondiabetic 54 543 34 85 30 9 * Feingold KR et al. Arterioscler Thromb 1992; 12:1496-1502. ** Selby JV et al. Circulation 1993; 88:381-387. Slide Source LipidsOnline www.lipidsonline.org
  • Small Dense LDL and CHD: Potential Atherogenic Mechanisms  Increased susceptibility to oxidation  Increased vascular permeability  Conformational change in apo B  Decreased affinity for LDL receptor  Association with insulin resistance syndrome  Association with high TG and low HDL Austin MA et al. Curr Opin Lipidol 1996;7:167-171. Slide Source LipidsOnline www.lipidsonline.org
  • Hypertriglyceridemia and CHD Risk: Associated Abnormalities  Accumulation of chylomicron remnants  Accumulation of VLDL remnants  Generation of small, dense LDL-C  Association with low HDL-C  Increased coagulability -  plasminogen activator inhibitor (PAI-1) -  factor VIIc - Activation of prothrombin to thrombin Slide Source LipidsOnline www.lipidsonline.org
  • TG Metabolism in CHD: Studies in the Postprandial State Corrected for Fasting TG (mg/dL) 400 300 Uncorrected CHD Cases 300 TG Level* 200 CHD Cases 200 Controls 100 0 0 100 Controls 2 4 0 0 6 8 2 Hours after Test Meal 4 6 8 Error bars = SEM Patsch JR et al. Arterioscler Thromb 1992;12:1336-1345. Slide Source LipidsOnline www.lipidsonline.org
  • Factors Promoting Thromboembolic Disease in Diabetes  Increased plasma fibrinogen  Increased plasminogen activator inhibitor 1  Increased platelet aggregability Thompson SG et al. N Engl J Med 1995;332:635-641. Slide Source LipidsOnline www.lipidsonline.org
  • Adverse Effects on Balance Between Thrombosis and Fibrinolysis in Subjects with Diabetes  Predisposition to thrombosis - Platelet hyperaggregability - Elevated concentrations of procoagulants - Decreased concentration and activity of antithrombotic factors  Predisposition to attenuation of fibrinolysis - Decreased t-PA activity - Increased PAI-1 - Decreased concentrations of α2-antiplasmin Sobel BE. Circulation 1996;93:1613-1615. Slide Source LipidsOnline www.lipidsonline.org
  • PAI-1 Activity in Blood in Patients with Type 2 Diabetes PAI-1 Activity (AU/mL) 20 15 No Diabetes Diabetes 10 5 0 Lean PAI-1 = plasminogen activator inhibitor type 1 McGill JB et al. Diabetes. 1994;43:104-109. Obese Slide Source LipidsOnline www.lipidsonline.org
  • Elevation of PAI-1 Induced by Hyperinsulinemia, Hyperglycemia, and Increased FFA in Blood of Normal Subjects PAI-I (mg/mL) 21 18 Infusion of glucose and intralipid 15 12 * 9 6 3 0 0 Values are mean + SD 2 4 6 Time (h) *P<0.05 vs saline infusions in same subjects Calles-Escandon J et al. Diabetes. 1998;47:290-293. 8 10 12 Slide Source LipidsOnline www.lipidsonline.org
  • Pharmacologic Agents for Treatment of Dyslipidemia Effect on lipoprotein LDL HDL Triglyceride First-line agents  HMG CoA reductase inhibitor  Fibric acid derivative Second-line agents  Bile acid binding resins  Nicotinic acid In diabetic patients, nicotinic acid should be restricted to <2g/day. Short-acting nicotinic acid is preferred. American Diabetes Association. Diabetes Care 2000;23(suppl 1):S57-S60. Slide Source LipidsOnline www.lipidsonline.org
  • Order of Priorities for Treatment of Diabetic Dyslipidemia in Adults*  LDL cholesterol lowering* - First choice: HMG CoA reductase inhibitor (statin) - Second choice: Bile acid binding resin or fenofibrate  HDL cholesterol raising - Behavior interventions such as weight loss, increased physical activity and smoking cessation - Glycemic control - Difficult except with nicotinic acid, which is relatively contraindicated, or fibrates  Triglyceride lowering - Glycemic control first priority - Fibric acid derivative (gemfibrozil, fenofibrate) - Statins are moderately effective at high dose in hypertriglyceridemic subjects who also have high LDL cholesterol * Decision for treatment of high LDL before elevated triglyceride is based on clinical trial data indicating safety as well as efficacy of the available agents. Slide Source Adapted from American Diabetes Association. Diabetes Care 2000;23(suppl 1):S57-S60. LipidsOnline www.lipidsonline.org
  • Update on the Metabolic Syndrome Steven Haffner, MD Slide Source LipidsOnline www.lipidsonline.org
  • Metabolic Syndrome Increases Risk for CHD and Type 2 Diabetes High LDL-C Metabolic Syndrome Type 2 Diabetes Coronary Heart Disease Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497. Slide Source LipidsOnline www.lipidsonline.org
  • High Risk of Impaired Glucose Tolerance and Type 2 Diabetes by OGTT in Post-MI Patients without Known Diabetes % of Patients 100 IGT n = 181 80 60 40 New DM 35% 40% 31% 25% 20 0 At discharge 3 mo later Norhammar A et al. Lancet 2002;359:2140-2144. At discharge 3 mo later Slide Source LipidsOnline www.lipidsonline.org
  • Increased Metabolic Syndrome in Prediabetic Subjects: Baseline Risk Factors in Subjects with Normal Glucose Tolerance at Baseline according to Conversion Status at 8-Year Follow-up: San Antonio Heart Study Conversion Status at Follow-up Diabetes (n=18) Normal (n=490) P 28.2 ± 1.1 27.2 ± 0.2 .472 Centrality* 1.38 ± 0.09 1.16 ± 0.2 .472 TG (mmol) 1.83 ± 0.12 1.26 ± 0.10 .006 HDL-C (mmol) 1.14 ± 0.07 1.28 ± 0.02 .045 SBP (mm Hg) 116.8 ± 3.0 108.8 ± 0.8 .004 5.28 ± 0.1 5.00 ± 0.02 .032 157 ± 27 81 ± 5 .006 BMI (kg/m2) Fasting glucose (mmol) Fasting insulin (pmol) * Ratio of subscapular to triceps skinfolds Haffner SM et al. JAMA 1990;263:2893-2898. Slide Source LipidsOnline www.lipidsonline.org
  • Elevated Risk of CVD Prior to Clinical Diagnosis of Type 2 Diabetes: Nurses’ Health Study Relative Risk 6 5.02 5 3.71 4 2.82 3 2 1 1 0 Nondiabetic throughout the study Prior to diagnosis of diabetes Copyright © 2002 American Diabetes Association From Diabetes Care, Vol. 25, 2002; 1129-1134 Reprinted with permission from The American Diabetes Association. After diagnosis of diabetes Diabetic at baseline Slide Source LipidsOnline www.lipidsonline.org
  • Risk of Major CHD Event Associated with Insulin Quintiles in Nondiabetic Subjects: Helsinki Policemen Study Proportion without Major CHD Event 1.00 0.95 0.90 Q1 0.85 Q2 Log rank: Overall P = .001 Q5 vs. Q1 P < .001 0.80 0.75 Q3 Q4 Q5 0 0.70 0 5 10 Years Pyörälä M et al. Circulation 1998;98:398-404. 15 20 25 Slide Source LipidsOnline www.lipidsonline.org
  • CVD Risk Factors across HOMA-IR Quintiles: San Antonio Heart Study (Phase II) HOMA-IR Q1 Q2 Q3 Q4 Q5 HDL-C (mg/dl) 51.7 49.3 47.8 45.0 41.2 LDL-C (mg/dl) 115.7 119.3 125.0 128.1 124.8 Cholesterol (mg/dl) 188.0 191.6 197.9 200.8 199.0 Triglyceride (mg/dl) 105.7 116.6 129.7 145.4 187.2 Systolic BP (mm Hg) 114.9 116.5 118.3 119.3 123.0 69.0 70.4 71.9 73.1 75.4 Diastolic BP (mm Hg) Adjusted for age, sex, ethnicity All p(trend) < 0.0001; quintile cutpoints: 1.0, 1.6, 2.5, 4.8 Copyright © 2002 American Diabetes Association From Diabetes Care, Vol. 25, 2002; 1177-1184 Reprinted with permission from The American Diabetes Association. Slide Source LipidsOnline www.lipidsonline.org
  • Definitions of the Metabolic Syndrome  According to clinical outcomes  According to underlying causes  According to metabolic components  According to clinical criteria Slide Source LipidsOnline www.lipidsonline.org
  • Definition of Metabolic Syndrome: According to Underlying Causes  Insulin resistance (1999 WHO)  Insulin resistance syndrome  Lifestyle: especially obesity (NCEP ATP III)  Metabolic syndrome  Subclinical inflammation WHO. Definition, Diagnosis and Classification of Diabetes Mellitus and Its Complications: Report of a WHO Consultation. Geneva: WHO, 1999. | Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497. Slide Source LipidsOnline www.lipidsonline.org
  • Therapeutic Implications: According to Underlying Causes  Insulin resistance  Treat insulin resistance  Lifestyle: especially obesity  Prevent and treat obesity  Subclinical inflammation  Treat obesity  Statins, TZDs, etc. Slide Source LipidsOnline www.lipidsonline.org
  • ATP III: The Metabolic Syndrome Diagnosis is established when ≥ 3 of these risk factors are present Risk Factor Defining Level Abdominal obesity (Waist circumference) Men Women >102 cm (>40 in) >88 cm (>35 in) ≥150 mg/dl TG HDL-C Men Women <40 mg/dl <50 mg/dl Blood pressure ≥130/≥85 mm Hg Fasting glucose ≥110 mg/dl Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497. Slide Source LipidsOnline www.lipidsonline.org
  • Prevalence of the NCEP Metabolic Syndrome: NHANES III by Age Prevalence, % 50% 44% 44% Men 40% Women 30% 24% 23% 20% 10% 0% 8% 6% 20–70+ 20–29 20 30–39 30 40–49 50–59 Age, years Ford ES et al. JAMA 2002;287:356-359. 60–69 60 ≥70 Slide Source LipidsOnline www.lipidsonline.org
  • Prevalence of the NCEP Metabolic Syndrome: NHANES III by Sex and Race/Ethnicity White African American Mexican American Other Prevalence, % 40% 30% 28% 25% 26% 21% 20% 36% 23% 20% 16% 10% 0% Men Ford ES et al. JAMA 2002;287:356-359. Women Slide Source LipidsOnline www.lipidsonline.org
  • Prevalence of CHD by the Metabolic Syndrome and Diabetes in the NHANES Population Age 50+ 25% CHD Prevalence 19.2% 20% 13.9% 15% 10% 8.7% 7.5% 5% 0% No MS/No DM % of Population = 54.2% MS/No DM 28.7% Alexander CM et al. Diabetes 2003;52:1210-1214.. DM/No MS 2.3% DM/MS 14.8% Slide Source LipidsOnline www.lipidsonline.org
  • ATP III Metabolic Syndrome: Therapeutic Implications  Focus on obesity (especially abdominal obesity) as the underlying cause of the metabolic syndrome  Therefore, prevent development of obesity in the general population  Also, treat obesity in the clinical setting (NHLBI/NIDDK Obesity Education Initiative) Slide Source LipidsOnline www.lipidsonline.org
  • Different Components of the NCEP Metabolic Syndrome Predict CHD: NHANES Prediction of CHD Prevalence using Multivariate Logistic Regression Odds Ratio Lower 95% Limit Upper 95% Limit Waist circumference 1.13 0.85 1.51 Triglycerides 1.12 0.71 1.77 HDL cholesterol* 1.74 1.18 2.58 Blood pressure* 1.87 1.37 2.56 Impaired fasting glucose 0.96 0.60 1.54 Diabetes* 1.55 1.07 2.25 Metabolic syndrome 0.94 0.54 1.68 Variable *Significant predictors of prevalent CHD Copyright © 2003 American Diabetes Association From Diabetes, Vol. 52, 2003; 1210-1214 Reprinted with permission from The American Diabetes Association. Slide Source LipidsOnline www.lipidsonline.org
  • Different Components of the NCEP Metabolic Syndrome Predict Diabetes: San Antonio Heart Study Risk of Type 2 Diabetes per Unit Change in Risk Trait Levels 8% FPG per mg/dl 2% SBP per mm Hg HDL-C per mg/dl decrease 4% 7% BMI per kg/m2 0% 2% 4% Stern MP et al. Ann Intern Med 2002;136:575-581. 6% 8% 10% Slide Source LipidsOnline www.lipidsonline.org
  • WHO Metabolic Syndrome Definition 1999: Based on Clinical Criteria  Insulin resistance (type 2 diabetes, IFG, IGT)*  Plus any 2 of the following:  Elevated BP (≥140/90 or drug Rx)  Plasma TG ≥150 mg/dl  HDL <35 mg/dl (men); <40 mg/dl (women)  BMI >30 and/or W/H >0.9 (men), >0.85 (women)  Urinary albumin >20 mg/min; Alb/Cr >30 mg/g * Note that 1999 WHO uses hyperinsulinemic euglycemic clamp whereas 1998 WHO and EGIR use HOMA-IR. WHO. Definition, Diagnosis and Classification of Diabetes Mellitus and Its Complications: Report of a WHO Consultation. Geneva: WHO, 1999. Slide Source LipidsOnline www.lipidsonline.org
  • Must Insulin Resistance be Present for a Patient to Have the Metabolic Syndrome?  WHO 1999 clinical definition  Yes  ATP III 2001 clinical definition  No, but it is usually present  Multiple metabolic risk factors are sufficient  Obesity can produce the metabolic syndrome without insulin resistance WHO. Definition, Diagnosis and Classification of Diabetes Mellitus and Its Complications: Report of a WHO Consultation. Geneva: WHO, 1999. | Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497. Slide Source LipidsOnline www.lipidsonline.org
  • WHO Metabolic Syndrome Definition 1999: Therapeutic Implications  Focus on insulin resistance as the underlying cause of the metabolic syndrome  More emphasis on the genetic basis of the metabolic syndrome rather than obesity  Leads to increased thinking about the use of drugs to treat insulin resistance in patients with the metabolic syndrome Slide Source LipidsOnline www.lipidsonline.org
  • Therapeutic Implications of Definition of Metabolic Syndrome  If focus is on obesity as underlying cause  Prevent and treat obesity  If focus is on insulin resistance as underlying cause  Treat insulin resistance  If focus is on metabolic risk factors  Treat individual risk factors Slide Source LipidsOnline www.lipidsonline.org
  • Criteria for Comparing Different Definitions of Metabolic Syndrome  Risk of:  CHD  DM  Relation to:  Insulin resistance  Obesity  Prevalence in community could differ by race  How simple is the definition? Slide Source LipidsOnline www.lipidsonline.org
  • Intensity of Therapy Should be Proportionate to Level of Risk  What is the impact of the metabolic syndrome on health outcomes?  Cardiovascular disease  Type 2 diabetes Slide Source LipidsOnline www.lipidsonline.org
  • Cumulative Hazard, % Cardiovascular Disease Mortality Increased in the Metabolic Syndrome: Kuopio Ischaemic Heart Disease Risk Factor Study 15 10 Cardiovascular Disease Mortality Metabolic Syndrome: RR (95% CI), 3.55 (1.98–6.43) YES 5 0 0 NO 2 4 6 8 Follow-up, y Lakka HM et al. JAMA 2002;288:2709-2716. 10 12 Slide Source LipidsOnline www.lipidsonline.org
  • Cox Proportional Hazard Ratios (and 95% Confidence Intervals) Predicting All-Cause and Cardiovascular Mortality: San Antonio Heart Study 14-Year Followup NCEP MetS WHO MetS All Cause 1.43 (1.10–1.87) 1.25 (0.96–1.63) CVD 2.55 (1.75–3.72) 1.64 (1.13–2.37) All Cause 1.11 (0.74–1.67) 0.87 (0.57–1.33) CVD 2.04 (1.14–3.63) 0.77 (0.38–1.55) Total Population Disease Free* * Those without diabetes, cardiovascular disease, or cancer. Adjusted for age, gender, and ethnic group. Hunt KJ et al. Diabetes 2003;52:A221-A222. Slide Source LipidsOnline www.lipidsonline.org
  • % in Lowest Quartile of Si Comparison of NCEP and 1999 WHO Metabolic Syndrome to Identify Insulin-Resistant Subjects: IRAS 90 80 70 60 50 40 30 20 10 0 Overall Hispanics Non-Hispanic whites African Americans Neither NCEP Only Hanley AJ et al. Diabetes 2003;52:2740-2747. WHO Only Both Slide Source LipidsOnline www.lipidsonline.org
  • CRP Adds Prognostic Information at All Levels of Risk as Defined by the Framingham Risk Score 25 20 15 ks R ev t a e R i i l 10 >3.0 5 0 1.0–3.0 <1.0 hs-CRP 10+ 5–9 2–4 0–1 (mg/L) Framingham 10-Year Risk (%) Ridker PM et al. N Engl J Med 2002;347:1557-1565. Copyright © 2002 Massachusetts Medical Society. All rights reserved. Adapted with permission. Slide Source LipidsOnline www.lipidsonline.org
  • Partial Spearman Correlation Analysis of Inflammation Markers with Variables of IRS Adjusted for Age, Sex, Clinic, Ethnicity, and Smoking Status: IRAS CRP WBC BMI 0.40‡ 0.17‡ 0.22‡ Waist 0.43‡ 0.18‡ 0.27‡ Systolic BP 0.20‡ 0.08* 0.11† Fasting glucose 0.18‡ 0.13‡ 0.07* Fasting insulin 0.33‡ 0.24‡ 0.18‡ –0.37‡ –0.24‡ –0.18‡ Si Fibrinogen *P<0.05, †P<0.005, ‡P<0.0001 CRP=C-reactive protein; IRS=insulin-resistance syndrome; WBC=white blood cell count. Festa A et al. Circulation 2000;102:42–47. Slide Source LipidsOnline www.lipidsonline.org
  • e u a V nae M l Mean Values of CRP by Number of Metabolic Disorders (Dyslipidemia, Upper Body Adiposity, Insulin Resistance, Hypertension): IRAS 1.6 1.4 1.2 1.0 0.8 0.6 0.4 0.2 0.0 0 1 2 3 Number of Metabolic Disorders Festa A et al. Circulation 2000;102:42–47. 4 Slide Source LipidsOnline www.lipidsonline.org
  • Five-Year Incidence of Type 2 Diabetes Stratified by Quartiles of Inflammatory Proteins: IRAS Quartiles: Incidence, % 25 1st P=0.06 2nd P=0.001 3rd 4th P=0.001 20 15 10 5 0 Fibrinogen Festa A et al. Diabetes 2002;51:1131-1137. CRP PAI-1 Slide Source LipidsOnline www.lipidsonline.org
  • The Effect of Rosiglitazone on CRP Difference = –21.8 (95% CI: –34.7, –5.6) Change from Baseline to Week 26, % Difference = –26.8 (95% CI: –39.7, –21.8) 0 n=95 n=124 n=134 Rosiglitazone 4 mg/d Rosiglitazone 8 mg/d -10 -20 -30 -40 -50 Placebo Haffner SM et al. Circulation 2002;106:679-684. Slide Source LipidsOnline www.lipidsonline.org
  • The Effect of Rosiglitazone on IL-6 Difference = 0.0 (95% CI: –9.0, 10.0) Change from Baseline to Week 26, % Difference = –1.9 (95% CI: –11.3, 9.3) 0 n=91 n=120 n=132 Placebo Rosiglitazone 4 mg/d Rosiglitazone 8 mg/d -10 -20 -30 -40 -50 Haffner SM et al. Circulation 2002;106:679-684. Slide Source LipidsOnline www.lipidsonline.org
  • Reduction of CRP Levels with Statin Therapy (n=22) 6 ** p<0.025 vs. Baseline p<0.025 vs. Baseline 5 * 4 * 3 * ) L/ g m P RC s h ( - 2 1 0 Baseline Pravastatin (40 mg/d) Jialal I et al. Circulation 2001;103:1933-1935. Simvastatin (20 mg/d) Atorvastatin (10 mg/d) Slide Source LipidsOnline www.lipidsonline.org
  • Summary  Insulin resistance is related to increased PAI-1, fibrinogen, and CRP levels cross-sectionally  Increased levels of PAI-1, CRP, and fibrinogen (weak) predict the development of type 2 diabetes. In some analyses, these associations are independent of obesity and insulin resistance  Rosiglitazone, a TZD, decreases levels of PAI-1, CRP, and MMP-9 Slide Source LipidsOnline www.lipidsonline.org
  • Does Lipid and Blood Pressure Therapy Work in Subjects with the Metabolic Syndrome?  Diabetic subjects  Blood pressure: YES  Statin therapy: YES  Nondiabetic subjects  Little data available Slide Source LipidsOnline www.lipidsonline.org
  • CHD Prevention Trials with Statins in Diabetic Subjects: Subgroup Analyses Study Drug No. CHD Risk Reduction Overall CHD Risk Reduction in Diabetics Primary Prevention AFCAPS/TexCAPS Lovastatin 155 37% 43% (NS) Simvastatin 2912 24% 33% (p=.0003) CARE Pravastatin 586 23% 25% (p=.05) 4S Simvastatin 202 32% 55% (p=.002) LIPID Pravastatin 782 25% 19% 4S Reanalysis Simvastatin 483 32% 42% (p=.001) HPS Simvastatin 1981 24% 15% HPS Secondary Prevention Downs JR et al. JAMA 1998;279:1615-1622. | HPS Collaborative Group. Lancet 2003;361:2005-2016. | Goldberg RB et al. Circulation 1998;98:2513-2519. | Pyörälä K et al. Diabetes Care 1997;20:614-620. | LIPID Study Group. N Engl J Med 1998;339:1349Slide Source LipidsOnline 1357. | Haffner SM et al. Arch Intern Med 1999;159:2661-2667. www.lipidsonline.org
  • Completed Clinical Trials with Antihypertensive Agents in Diabetes Trial Diabetic/Total Results SHEP 583/4736 Beneficial GISSI-3 2790/18,131 Beneficial Syst-Eur 492/4695 Beneficial 1501/18,790 Beneficial UKPDS 1148 Beneficial CAPPP 572/10,985 Beneficial HOT Curb JD et al. JAMA 1996;276:1886-1892. | Zuanetti G et al. Circulation 1997;96:4239-4245. | Staessen JA et al. Am J Cardiol 1998;82:20R–22R. | Hansson L et al. Lancet 1998;351:1755-1762. | UKPDS Group. BMJ 1998;317:703Slide Source LipidsOnline 713. | Hansson L et al. Lancet 1999;353:611-616. www.lipidsonline.org
  • “Metabolic Syndrome” in 4S Lipid Triad 40 RR=0.48 (0.33–0.69) Isolated ↑ LDL-C RR=0.86 (0.59–1.26) Event Rate, % 36.9 Placebo 30 20 Simvastatin 19.0 18.0 20.3 10 0 221 237 Ballantyne CM et al. Circulation 2001;104:3046-3051. 261 284 Slide Source LipidsOnline www.lipidsonline.org
  • Patients Reaching IntensiveTreatment Goals at Mean 7.8 y, (%) Efficacy of Multiple Risk Factor Intervention in High-Risk Subjects (Type 2 Diabetes with Microalbuminuria): Steno-2 Intensive Therapy 80 70 P<0.001 60 Conventional Therapy P=0.21 P=0.19 P=0.001 50 40 30 20 P=0.06 10 0 Glycosylated Cholesterol Triglycerides Systolic BP Diastolic BP hemoglobin <175 mg/dl <150 mg/dl <130 mm Hg <80 mm Hg <6.5% Slide Source LipidsOnline Gæde P et al. N Engl J Med 2003;348:383-393. Copyright © 2003 Massachusetts Medical Society. All rights reserved. www.lipidsonline.org
  • Composite Endpoint of Death from CV Causes, Nonfatal MI, CABG, PCI, Nonfatal Stroke, Amputation, or Surgery for PAD: STENO-2 Primary Composite Endpoint (%) 60 P=0.007 50 Hazard ratio = 0.47 (95% CI, 0.24–0.73; P=0.008) 40 Conventional Therapy 30 20 Intensive Therapy 10 0 0 12 24 36 48 60 72 Months of Follow-up Gæde P et al. N Engl J Med 2003;348:383-393. Copyright © 2003 Massachusetts Medical Society. All rights reserved. 84 96 Slide Source LipidsOnline www.lipidsonline.org
  • Summary: Metabolic Syndrome  The metabolic syndrome predicts the development of both diabetes and CHD  Insulin resistance and obesity characterize most individuals subjects with the metabolic syndrome, although not required features of the NCEP metabolic syndrome  Initial therapy for the metabolic syndrome should consist of caloric restriction and increased physical activity  Conventional cardiovascular risk factors such as lipids and blood pressure should be treated in individuals with the metabolic syndrome, although no recommendations have so far suggested intensification of risk factor management  No consensus exists on whether insulin sensitizers should be used in nondiabetic individuals with the metabolic syndrome Slide Source LipidsOnline www.lipidsonline.org
  • Slide Source LipidsOnline www.lipidsonline.org