Prevention Conference VI: Diabetes and Cardiovascular Disease: executive summary: conference proceeding for healthcare professionals from a special writing group of the American Heart Association.

Abstract

HomeCirculationVol. 105, No. 18Diabetes and Cardiovascular Disease Executive Summary Conference Proceeding for Healthcare Professionals From a Special Writing Group of the American Heart Association Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree AccessReview ArticlePDF/EPUBDiabetes and Cardiovascular Disease Executive Summary Conference Proceeding for Healthcare Professionals From a Special Writing Group of the American Heart Association Scott M. Grundy, MD, PhD, Barbara Howard, PhD, Sidney SmithJr, MD, Robert Eckel, MD, Rita Redberg, MD and Robert O. Bonow, MD Scott M. GrundyScott M. Grundy Search for more papers by this author , Barbara HowardBarbara Howard Search for more papers by this author , Sidney SmithJrSidney SmithJr Search for more papers by this author , Robert EckelRobert Eckel Search for more papers by this author , Rita RedbergRita Redberg Search for more papers by this author and Robert O. BonowRobert O. Bonow Search for more papers by this author Originally published7 May 2002https://doi.org/10.1161/01.CIR.0000013952.86046.DDCirculation. 2002;105:2231–2239is corrected byCorrectionThe American Heart Association (AHA) sponsored a scientific conference entitled “Prevention VI: Diabetes and Cardiovascular Disease” on January 18 to 20, 2001, in Orlando, Fla. The purpose of this conference was to create a report that would assist the AHA in the development of an agenda to reduce cardiovascular diseases (CVDs) that are associated with diabetes. The report has been developed by working group sections. The topics to be covered by each working group were introduced by a series of presentations, and this was followed by an extensive discussion of a team of working group members. The primary objectives of this meeting were as follows:To review the scope of CVD in patients with diabetesTo review current concepts of the pathophysiology of cardiovascular complications in patients with diabetesTo review recent clinical trials demonstrating the control of cardiovascular risk factors for the prevention of complications in patients with diabetesTo review approaches to the assessment of cardiovascular risks associated with diabetesTo review current evidence for efficacy of medical management of the cardiovascular complications accompanying diabetesTo review efficacy and safety of standard invasive (or surgical) procedures for the treatment of the cardiovascular complications of diabetesThe key findings of each working group are presented in this Executive Summary of the conference. The full conference report with references is available online at http://www.circulationaha.org in the May 7, 2002, issue of Circulation.Writing Group I: EpidemiologyThe prevalence of diabetes in the United States is increasing rapidly, and individuals with diabetes are at high risk for cardiovascular disorders that affect the heart, brain, and peripheral vessels. Although CVD accompanying diabetes is on the rise, many unanswered questions remain concerning the temporal relations between diabetes and CVD, the contributions of conventional risk factors, and the role of diabetes-specific risk factors.Almost 35 million Americans—20% of all people in the middle-adult years and 35% of the entire older population—have some degree of abnormal glucose tolerance; this higher-risk group will account for a significant portion of CVD and premature mortality in the United States. The increasing frequency of obesity and sedentary lifestyles, major underlying risk factors for type 2 diabetes in both developed and developing countries, portends that diabetes will continue to be a growing clinical and public health problem. This is true both for the United States and worldwide.The prevalence of, incidence of, and mortality from all forms of CVD are 2- to 8-fold higher in persons with diabetes than in those without diabetes. The proportion of new-onset CVD attributable to diabetes or impaired glucose tolerance ranges from ≈14% in whites to 50% to 80% in American Indians. Diabetes, notably type 2 diabetes, is on the rise in children and adolescents, thereby increasing the likelihood that they will develop premature coronary heart disease (CHD). The major CVD risk factors—elevated low-density lipoprotein (LDL) cholesterol, hypertension, smoking, and sex—remain important determinants of CVD in patients with diabetes. In addition, the emerging risk factors—albuminuria, fibrinogen, degree of glycemia, extent of insulin resistance, and presence of subclinical atherosclerosis—further appear to affect risk in individuals with diabetes.Early detection of CVD risk factors in patients with established diabetes and early intervention should delay onset of CVD in this population. Determinants of progression of coronary atherosclerosis and development of clinical events in patients with diabetes need to be better defined. Detection and intervention with regard to the atherogenic metabolic abnormalities and glucose intolerance that precede development of diabetes would be even more beneficial. Gene-environment interactions should also be explored as they relate to diabetes and CVD; in particular, the impact of sociocultural factors must be considered in risk assessment and prevention strategies. Improved measures to identify individuals at risk for diabetes and CVD must be evaluated; in particular, in risk assessment, the American Diabetes Association (ADA) category of impaired fasting glucose and the post–glucose-challenge level in older individuals may be underused. Whether methods of measuring atherosclerosis and vascular disease, such as carotid ultrasound, echocardiography, magnetic resonance imaging, and ankle-brachial index, will augment risk assessment in patients with diabetes requires additional evaluation.Writing Group I recommends, on the basis of the ominous rise of diabetes and its associated CVD, that the AHA institute programs to achieve the following: monitor the burden of CVD attributable to diabetes; monitor temporal changes in glucose homeostasis; test and target CVD prevention strategies with regard to diabetic children, adolescents, and those with impaired glucose tolerance; develop diet and exercise programs to mitigate CVD risk in diabetic patients, with an aggressive focus on the newly diagnosed; continue research into lifestyle and biochemical CVD risk factors in diabetes; and elucidate the economic burden of diabetes-associated CVD.Writing Group II: Pathogenesis of Atherosclerosis in DiabetesThis writing group found that the pathogenesis of atherosclerosis in diabetes is complex and multifactorial. Five general areas of mechanism were defined. The first, metabolic factors, exists on a foundation of hyperglycemia that results from both insulin deficiency and insulin resistance. The insulin resistance syndrome is a composite of numerous covariates that include increased flux of free fatty acids, dyslipidemia (increased very-low-density lipoprotein and decreased high-density lipoprotein and small dense lipoproteins), hyperinsulinemia, and hypertension. Importantly, hyperglycemia results in increased rates of glycation and oxidation. Excessive oxidation/glucoxidation is a consequence of abundant protein glycation in the setting of increased oxygen radicals with subsequent advanced glycation end-product accumulation. An increase in lipid and lipoprotein peroxidation also occurs, a process that likely contributes to foam cell formation within the arterial wall. Endothelial dysfunction is associated with hyperglycemia, dyslipidemia, hypertension, and atherosclerosis. Although endothelial dysfunction is not atherosclerosis, it may be an important pathophysiological precursor. Insulin resistance may be a contributor to endothelial dysfunction. Moreover, the process of inflammation probably is increased in diabetes. This in part relates to the excessive amount of adipose tissue, an important source of interleukin-6, a precursor for C-reactive protein generation. Cytokines not only contribute to oxidative metabolism in tissues but also generate growth factors that are important to the response of the arterial wall to injury. These growth factors stimulate the proliferation and migration of smooth muscle cells and induce platelet aggregation. Diabetes is also considered to be a prothrombotic state. This is an imbalance in prothrombotic mechanisms and antifibrinolytic processes. Debates remain as to differences in the plaque in type 1 versus type 2 diabetes. Overall, a better understanding of the pathophysiological mechanisms of atherosclerosis may provide a better understanding of the process in general.Writing Group III: Risk AssessmentWriting Group III reviewed all of the current data on risk assessment techniques for CVD with special reference to the data for patients with diabetes. It was first established that the goal of risk assessment would be to identify subclinical CVD in patients with diabetes, which would lead to a change in management that would result in an improvement in morbidity and/or mortality. This group reviewed existing guidelines, then evaluated the data on office-based risk factor assessment, as well as diagnostic imaging techniques.Patients with diabetes are known to be at increased risk of CVD; moreover, patients with diabetes have an increased risk of cardiac events once the diagnosis of CVD has been established. Because of this increased risk, the AHA designates diabetes as a “coronary risk equivalent” and indicates that patients with diabetes belong in the same risk category as patients with known CVD. Thus, Writing Group III began with the premise that all patients with diabetes should be treated with aggressive risk factor modification.Principles of ScreeningScreening is defined here as the detection of disease in asymptomatic persons. Because screening tests are intended for widespread application, they are should be rapid and inexpensive. In addition, to be useful, the results of testing should lead to a change in management, and the results of testing should improve outcome.Current Clinical Practice GuidelinesThere are several existing published guidelines for risk assessment in patients with CVD or those at risk for CVD. The French Guideline for Detection of Silent Myocardial Ischemia in patients with diabetes suggests that screening for silent myocardial ischemia should be performed in patients with diabetes and 1 additional factor: peripheral arterial disease, proteinuria, or the presence of major CVD risk factors. They specifically mention the use of exercise treadmill testing or thallium stress testing. The American College of Cardiology (ACC)/AHA Guidelines for Exercise Testing give screening by exercise treadmill testing in patients with diabetes a data quality rating of IIb, ie, its usefulness or efficacy is less well established by evidence or opinion. They add that exercise testing “might be useful in people with heightened pretest risk.” The ADA/ACC Consensus Statement on Diabetes and CVD suggests that noninvasive cardiac testing be performed in patients with diabetes and 1 additional factor: peripheral arterial disease, cerebrovascular disease, rest ECG changes, or presence of 2 or more major CVD risk factors. The authors of this report state that because of a lack of definitive data, recommendations must be made on the basis of “clinical judgment and subgroup analysis.” It is notable that the solid reasons for or goals of management accompanying detection of subclinical disease are not defined in any of these documents.Risk Assessment StrategyRisk assessment should begin with a careful medical history, with special attention paid to elicit symptoms of atherosclerotic disease, such as angina, claudication, or erectile dysfunction. A dietary assessment and questions on physical activity level must be included. Next is a careful physical examination and an ECG to look for evidence of left ventricular hypertrophy and ST-T changes, both of which are accompanied by increased cardiovascular risk.There are many noninvasive tests that are being evaluated to determine their ability to predict cardiac risk. Writing Group III considered that any noninvasive test should provide risk prediction beyond that obtained by office-based risk assessment. Because diabetes is considered a risk equivalent for CHD by the AHA, a negative test result in a patient would not remove the patient from this high-risk category; conversely, a positive test would not change the already recommended aggressive approach to risk factor modification. The writing group nonetheless recognized that there may be special situations in which noninvasive testing would be beneficial, such as for patients with type 1 diabetes. The writing group did examine carefully all data on the following noninvasive tests; however, most of these data were not obtained in patients with diabetes.Ankle-Brachial Blood Pressure IndexThe ankle-brachial blood pressure index (ABI) is performed by measuring blood pressure in both arms and the posterior tibial and dorsalis pedis arteries and computing an ankle/average arm blood pressure ratio. An ABI <0.90 constitutes a diagnosis of peripheral arterial disease. A low ABI has been shown to provide incremental independent predictive power for CVD risk in population-based studies. These latter studies provide convincing evidence that the ABI is a useful noninvasive measure for the detection of subclinical peripheral arterial disease; moreover, a low ABI provides incremental information beyond that provided by standard CVD risk factors, especially in people aged 50 years and older with increased risk for CVD, such as those with diabetes. Thus far, studies have included too few subjects with diabetes to allow reliable estimations of the contribution of this noninvasive test to the prediction of the future risk of CVD mortality and morbidity among asymptomatic subjects with diabetes. Moreover, because the presence of diabetes counts as a CHD risk equivalent, the management of risk factors will not be modified by the detection of a low ABI.Carotid Intima-Media ThicknessCarotid intima-media thickness measurements use B-mode ultrasound to measure the lumen and wall of the carotid artery. Prospective population-based studies have shown that in asymptomatic subjects, intima-media thickness provides incremental predictive information on the future risk of CVD. However, these observations cannot be directly extrapolated to subjects with diabetes, in whom intima-media thickness has been found to be greater than in nondiabetic subjects.Electron-Beam Computed TomographyElectron-beam computed tomography measures coronary artery calcium, which is a marker for coronary atherosclerosis. It appears to be capable of detecting coronary artery calcification (CAC) in many asymptomatic patients with either type 1 or type 2 diabetes. Many asymptomatic subjects with diabetes, however, have been reported to have CAC scores of 0. CAC scores in some studies appear to have predictive power for likelihood of developing clinical CVD. Whether CAC scores predict future clinical events in asymptomatic patients with diabetes is not yet known, and such data are needed to help define a role for electron-beam computed tomography in asymptomatic patients with diabetes. The predictive value for clinical events in patients with diabetes is not well defined.Exercise Tolerance TestingIn subjects without diabetes, exercise testing appears to be predictive of prognosis, ie, prediction of likelihood of experiencing major coronary events. In the same way, exercise single photon emission computed tomography (SPECT) has independent predictive power. However, there is a paucity of data on the predictive power of exercise testing in patients with diabetes. Limited data nonetheless suggest that whereas symptoms may be unreliable for detection of ischemic heart disease in patients with diabetes, ischemic findings on exercise ECG appear to be at least as predictive of prognosis in patients with diabetes (and possibly indicative of even worse outcome) than in nondiabetic patients. However, there are few outcome data that document the utility of early identification of asymptomatic CVD in patients with diabetes. This may not be true, however, for asymptomatic persons without diabetes. For example, in the Lipid Research Clinics–Coronary Primary Prevention Trial, exercise testing in asymptomatic, hypercholesterolemic subjects identified a high-risk group, and cholesterol-lowering therapy significantly lowered their risk.Magnetic Resonance ImagingHigh-resolution magnetic resonance imaging can differentiate plaque components, and under some circumstances, it may be able to identify vulnerable plaque. Although this technique appears promising, there are few data on its power to predict future CVD events at this time. The assessment of atherosclerotic plaques by imaging techniques may prove valuable for the identification of vulnerable plaques. In vivo high-resolution, multicontrast magnetic resonance imaging holds promise for noninvasively imaging vulnerable plaques and characterizing the different components in all arteries, including the coronary arteries. Magnetic resonance allows serial evaluation assessment of the progression and regression of atherosclerosis over time. Recommendation of this technique for risk assessment awaits more data.Outcomes and Risk AssessmentTaken together, the data suggest that several measures may be useful predictors of CVD events; however, their incremental value to office-based risk assessment and cost-effectiveness for screening of patients with diabetes have not been evaluated fully. Currently, there are no data to show benefit of early identification of subclinical atherosclerotic disease in the asymptomatic stage in patients with diabetes. Because patients with diabetes are already considered to be at high risk for future CVD events, routine risk assessment by noninvasive testing is not recommended for the purpose of determining intensity of risk factor reduction. Furthermore, few data are available to justify noninvasive testing for subclinical disease for the purpose of invasive intervention in asymptomatic patients.Future ResearchResearch is necessary to investigate the incremental value of noninvasive tests over office-based risk assessment for prediction of future risk for developing CVD. The role of noninvasive risk assessment in lifestyle changes (such as a heart-healthy diet and increased physical activity), medication use (prescription rates and compliance), and outcomes (both hard events, such as nonfatal myocardial infarction or death, and soft events, such as angina and revascularization) is essential. Cost-effectiveness analysis of various strategies is essential to make informed medical and policy decisions.Conclusions: Noninvasive Risk Assessment in Patients With DiabetesFor patients with diabetes, office-based assessment of risk factors is useful to define targets for intervention to reduce cardiovascular risk; additional noninvasive testing is not recommended on a routine basis at this time because it would not change management or lead to improvement in outcomes. However, there may be special considerations, such as patients with type I diabetes or elderly people with type 2 diabetes, in whom noninvasive testing would be useful for making management decisions. The realization of this possibility awaits further investigation.Writing Group IV: Lifestyle and Medical Management of Risk FactorsA high priority must be given to modification of the major risk factors for CVD in patients with diabetes. Increasing evidence indicates that controlling CVD risk factors will reduce onset of CVD and its complications in patients with diabetes. In the clinical management of patients with diabetes, attention must be given both to major risk factors (cigarette smoking, hypertension, elevated LDL cholesterol and diabetic dyslipidemia, and hyperglycemia) and to underlying risk factors (overweight/obesity, physical inactivity, and adverse nutrition). Writing Group IV reviewed these risk factors in light of current recommendations for management of risk factors in diabetes as presented by the ADA, the AHA, and the national education programs sponsored by the National Heart, Lung, and Blood Institute (Table). Table 1107391. Goals for Risk Factor Management in Patients With DiabetesRisk FactorGoal of TherapyRecommending BodyJNC VI indicates 6th report of the Joint National Committee on Prevention, Evaluation, and Treatment of High Blood Pressure; NHLBI, National Heart, Lung, and Blood Institute; ATP III, National Cholesterol Education Program Adult Treatment Panel III; HDL, high-density lipoprotein; and OEI, Obesity Education Initiative Expert Panel on Identification, Evaluation, and Treatment of Overweight and Obesity in Adults.Cigarette smokingComplete cessationADABlood pressure<130/85 mm HgJNC VI (NHLBI)<130/80 mm HgADALDL cholesterol<100 mg/dLATP III (NHLBI), ADATriglycerides 200–499 mg/dLNon-HDL cholesterol <130 mg/dLATP III (NHLBI)HDL cholesterol <40 mg/dLRaise HDL (no set goal)ATP III (NHLBI)Prothrombotic stateLow-dose aspirin therapy (patients with CHD and other high-risk patients)ADAGlucoseHemoglobin A1c <7%ADAOverweight and obesity (BMI ≥25 kg/m2)Lose 10% of body weight in 1 yearOEI (NHLBI)Physical inactivityExercise prescription dependent on patient statusADAAdverse nutritionSee textADA, AHA, and NHLBI’s ATP III, OEI, and JNC VIMajor Risk FactorsCigarette SmokingCigarette smoking is a major risk factor for CVD, and when a smoking patient also has diabetes, this patient is doubly at risk for CVD. Thus, every effort must be made to convince patients with diabetes who smoke to give up the smoking habit.HypertensionElevated blood pressure is a major independent risk factor for CHD, stroke, chronic renal failure, and heart failure. The prevalence of hypertension is increased in patients with diabetes. Factors that contribute to hypertension in these patients include obesity, insulin resistance, hyperinsulinemia, and in many cases, renal disease. Microalbuminuria often accompanies hypertension but probably is an independent risk factor for CVD. The Sixth Report of the Joint National Committee for the Detection, Evaluation, and Treatment of Hypertension (JNC VI) singled out diabetes as a high-risk state deserving of more aggressive blood-pressure control. It set the blood pressure goal as a level of <130/<85 mm Hg (Table). The ADA recommends a goal of <130/<80 mm Hg. Therapeutic lifestyle changes (weight reduction, increased physical activity, lower salt intakes, increased fruit and vegetable consumption, and higher potassium intakes) are first-line therapy. Nonetheless, antihypertensive drugs, often in combination, commonly are required to achieve the goal of therapy. Most of the major drugs used to treat hypertension (diuretics, β-blockers, angiotensin converting enzyme [ACE] inhibitors, and calcium channel blockers) are effective in patients with diabetes. Thiazide diuretics preferably are used at lower doses. Although β-blockers may worsen insulin resistance and may mask symptoms of hyperglycemia, they are generally well tolerated by patients with diabetes and are indicated in those with recent myocardial infarction. Assiduous treatment of hypertension in patients with diabetes will delay progression of diabetic nephropathy and retinopathy. ACE inhibitors and angiotensin II receptor inhibitors will slow progression of diabetic nephropathy; they may be indicated in the presence of microalbuminuria.LDL Cholesterol and Diabetic DyslipidemiaPatients with diabetes commonly have 2 lipid disorders. First, a higher than optimal level of LDL cholesterol contributes to atherogenesis and coronary plaque rupture. The second disorder is a condition called diabetic dyslipidemia, which is characterized by a triad of lipid disorders: elevated triglycerides, small LDL particles, and low levels of high-density lipoprotein cholesterol. This lipid triad is especially common in patients with type 2 diabetes. Both LDL cholesterol and diabetic dyslipidemia deserve attention. The recently updated clinical guidelines of the National Cholesterol Education Program have set an optimal LDL cholesterol level (<100 mg/dL) as a goal of therapy in patients with diabetes. This goal for LDL cholesterol is advocated by the ADA. These guidelines further recommend that LDL-lowering drugs should be started simultaneously with dietary therapy when baseline LDL-cholesterol levels are ≥130 mg/dL in patients with diabetes. When LDL-cholesterol levels are near optimal (100 to 129 mg/dL), several therapeutic options are available, eg, intensification of LDL-lowering diet and/or drug therapy or more aggressive control of other lipid or nonlipid risk factors.For patients with diabetic dyslipidemia, LDL lowering, usually with statins, is the primary target. However, recent clinical trials of fibrate therapy provide suggestive evidence for benefit by modification of diabetic dyslipidemia in patients with type 2 diabetes and the metabolic syndrome. This observation raises the possibility that the combination of drug therapy with fibrates and statins will offer a greater risk reduction than can be achieved with LDL lowering alone.Prothrombotic StateMost patients with insulin resistance harbor a prothrombotic state, which is characterized by elevated plasma levels of plasminogen activator inhibitor-1 and other defects of coagulation. A prothrombotic state may interfere with endothelial function, promoting atherogenesis; furthermore, in cases of coronary plaque rupture, it can promote propagation of thrombi and thereby worsen acute coronary syndromes. The most readily available means to counteract the prothrombotic state is use of low-dose aspirin therapy. For patients with diabetes who have established CHD, aspirin therapy is almost always indicated. Aspirin therapy probably is prudent even for patients with diabetes without manifest CHD because of increased risk for acute coronary syndromes.HyperglycemiaBy current definition, diabetes is present when the fasting plasma glucose is confirmed to be ≥126 mg/dL. Fasting plasma glucose of 110 to 125 mg/dL, or impaired fasting glucose, often denotes the presence of the metabolic syndrome. Impaired fasting glucose carries increased risk for the individual to develop type 2 diabetes and macrovascular disease (CHD) but not microvascular disease. The specific contribution of impaired fasting glucose to CHD risk is uncertain. Risk for CHD rises even more when fasting glucose exceeds 126 mg/dL, and when levels are persistently above 126 mg/dL, microvascular disease begins to make its appearance. Control of hyperglycemia is mandatory for the prevention of microvascular disease (diabetic nephropathy, neuropathy, and retinopathy). Clinical trials in patients with diabetes of both types 1 and 2 confirm the benefit of good glycemic control in the prevention of diabetic microvascular complications. Whether glycemic control will reduce the risk for macrovascular complications has not been proved definitively through controlled clinical trials.The primary goal for glycemic therapy is to achieve a near-normal fasting glucose level and a hemoglobin A1c level <7% (Table). Glycemic therapy for type 2 diabetes usually begins with oral hypoglycemic agents (eg, metformin, sulfonylureas, or glitazones). After several years of therapy with oral agents, insulin therapy usually will be required to achieve the goals of hypoglycemic control.Underlying Risk FactorsOverweight and ObesityOverweight (body mass index 25 to 29.9 kg/m2) and obesity (body mass index ≥30 kg/m2) are major underlying causes of insulin resistance, the metabolic syndrome, and type 2 diabetes. Among body weight parameters, abdominal obesity, which is denoted by increased waist circumference (male ≥103 cm; female ≥88 cm), is closely associated with development of metabolic risk factors and type 2 diabetes. Weight management in patients with type 2 diabetes must remain one component of risk factor management.In clinical practice, attention should be given to several basic principles for weight management in patients with diabetes. A team approach that makes use of the expertise of physicians, nurses, registered dietitians, or other health professionals and pharmacists is required to achieve and maintain acceptable weight reduction. In general, “crash diets” to achieve rapid weight loss have been unsuccessful; weight regain has been the rule. Instead, slow weight reduction, with the aim to lose 10% of body weight over a period of 1 year, is more likely to produce long-term success.Physical inactivity contributes importantly to development of overweight/obesity, as reflected in the rising prevalence of obesity in our sedentary society. Physical inactivity impairs insulin sensitivity, worsens the metabolic syndrome, and enhances risk for CVD through other mechanisms that are mediated through cardiovascular fitness and function. In the management of patients with diabetes, increased physical activity constitutes a prime goal. The physical activity prescription depends on clinical judgment. At a minimum, however, when regular physical activity is not contraindicated, the usual prescription of 30 minutes of moderate-intensity exercise daily can be recommended. If more intense exercise can be tolerated without harm, it will provide a still greater benefit. Consideration should be given to taking advantage of existing professionally assisted programs in exercise (eg, cardiac rehabilitation) for appropriately selected patients with diabetes. For these patients, appropriate attention must be paid to the dangers of hypoglycemia rela