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(Circulation. 1999;100:1134-1146.)
© 1999 American Heart Association, Inc.

AHA Scientific Statement

Diabetes and Cardiovascular Disease

A Statement for Healthcare Professionals From the American Heart Association

Scott M. Grundy, MD, PhD, Chair; Ivor J. Benjamin, MD; Gregory L. Burke, MD; Alan Chait, MD; Robert H. Eckel, MD; Barbara V. Howard, PhD; William Mitch, MD; Sidney C. Smith, Jr, MD; James R. Sowers, MD

Key Words: AHA Scientific Statements • diabetes mellitus • risk factors • cardiovascular diseases

	Introduction

Top Introduction Clinical Presentations of... Scope of the Problem Diabetes as a Major... Diabetes and Specific CVD Covariate Risk Factors Risk Assessment in the... Clinical Evaluation Cardiovascular Clinical... Primary Prevention Implications for Treatment of... References

 
This statement examines the cardiovascular complications of diabetes mellitus and considers opportunities for their prevention. These complications include coronary heart disease (CHD), stroke, peripheral arterial disease, nephropathy, retinopathy, and possibly neuropathy and cardiomyopathy. Because of the aging of the population and an increasing prevalence of obesity and sedentary life habits in the United States, the prevalence of diabetes is increasing. Thus, diabetes must take its place alongside the other major risk factors as important causes of cardiovascular disease (CVD). In fact, from the point of view of cardiovascular medicine, it may be appropriate to say, "diabetes is a cardiovascular disease."

	Clinical Presentations of Diabetes Mellitus

Top Introduction Clinical Presentations of... Scope of the Problem Diabetes as a Major... Diabetes and Specific CVD Covariate Risk Factors Risk Assessment in the... Clinical Evaluation Cardiovascular Clinical... Primary Prevention Implications for Treatment of... References

 
The most prevalent form of diabetes mellitus is type 2 diabetes. This disorder typically makes its appearance later in life. The underlying metabolic causes of type 2 diabetes are the combination of impairment in insulin-mediated glucose disposal (insulin resistance) and defective secretion of insulin by pancreatic ß-cells. Insulin resistance develops from obesity and physical inactivity, acting on a substrate of genetic susceptibility.^{1 2} Insulin secretion declines with advancing age,^{3 4} and this decline may be accelerated by genetic factors.^{5 6} Insulin resistance typically precedes the onset of type 2 diabetes and is commonly accompanied by other cardiovascular risk factors: dyslipidemia, hypertension, and prothrombotic factors.^{7 8} The common clustering of these risk factors in a single individual has been called the metabolic syndrome. Many patients with the metabolic syndrome manifest impaired fasting glucose (IFG)⁹ even when they do not have overt diabetes mellitus.¹⁰ The metabolic syndrome commonly precedes the development of type 2 diabetes by many years¹¹ ; of great importance, the risk factors that constitute this syndrome contribute independently to CVD risk.

Recently, new criteria have been accepted for the diagnosis of diabetes.⁹ The upper threshold of fasting plasma glucose for the diagnosis of diabetes has been lowered from 140 mg/dL to 126 mg/dL. The upper threshold for normoglycemia likewise has been reduced from <115 to <110 mg/dL. A fasting plasma glucose of 110 to 125 mg/dL is now designated IGF. These changes removed the need for oral glucose tolerance testing for diagnosis of diabetes; a diagnosis rests entirely on confirmed elevations of fasting plasma glucose. Furthermore, the terms insulin-dependent diabetes mellitus and non–insulin-dependent diabetes mellitus have been replaced by type 1 diabetes and type 2 diabetes, respectively.

The other form of diabetes mellitus is type 1 diabetes, which follows immunologic destruction of pancreatic ß-cells.¹² Type 1 diabetes usually begins early in life and is often called juvenile diabetes. This form of diabetes frequently produces microvascular complications, nephropathy, and retinopathy,¹² but it also predisposes to CHD.¹³ Because type 2 diabetes occurs much more commonly than type 1 diabetes, the present statement will emphasize type 2 diabetes. Nonetheless, type 1 diabetes will be integrated into the overall strategy of cardiovascular risk reduction.

	Scope of the Problem

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At least 10.3 million Americans carry a diagnosis of diabetes mellitus.¹⁴ Another 5.4 million are estimated to have undiagnosed diabetes.¹⁴ Approximately 90% of patients with diabetes have the type 2 variety.¹⁴ The onset of type 2 diabetes usually precedes clinical diagnosis by several years.¹⁴ An increasing prevalence of type 2 diabetes cannot be divorced from the rising prevalence of obesity and physical inactivity in our society. An estimated 97 million adults in the United States are overweight or obese.¹⁵ Furthermore, 75% of adult Americans have minimal physical activity or daily exercise.¹⁶ Both excess body fat and physical inactivity predispose to type 2 diabetes. Several ethnic groups are particularly susceptible to type 2 diabetes: Hispanics, blacks, Native Americans, and Asians (especially South Asians).^{17 18 19 20} The growing ethnic diversity, including these groups, contributes to the increasing prevalence of type 2 diabetes in the United States.

	Diabetes as a Major Risk Factor

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A large body of epidemiological and pathological data documents that diabetes is an independent risk factor for CVD in both men and women.^{21 22 23} Women with diabetes seem to lose most of their inherent protection against developing CVD.^{21 24} CVDs are listed as the cause of death in 65% of persons with diabetes.²⁵ Diabetes acts as an independent risk factor for several forms of CVD. To make matters worse, when patients with diabetes develop clinical CVD, they sustain a worse prognosis for survival than do CVD patients without diabetes.^{26 27 28} These considerations have convinced the Scientific Advisory and Coordinating Committee of the American Heart Association (AHA) that diabetes mellitus deserves to be designated a major risk factor for CVD. This formal designation commits the AHA to a greater emphasis on diabetes as a risk factor in its scientific and educational programs. This statement provides the scientific rationale for the decision to classify diabetes as a major risk factor for CVD.

	Diabetes and Specific CVD

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Atherosclerotic CHD
Both type 1 diabetes and type 2 diabetes are independent risk factors for CHD.^{21 22 23} Moreover, myocardial ischemia due to coronary atherosclerosis commonly occurs without symptoms in patients with diabetes.²⁹ As a result, multivessel atherosclerosis often is present before ischemic symptoms occur and before treatment is instituted. A delayed recognition of various forms of CHD undoubtedly worsens the prognosis for survival for many diabetic patients.

Diabetic Cardiomyopathy
One reason for the poor prognosis in patients with both diabetes and ischemic heart disease seems to be an enhanced myocardial dysfunction leading to accelerated heart failure (diabetic cardiomyopathy).^{30 31 32 33 34 35 36 37} Thus, patients with diabetes are unusually prone to congestive heart failure. Several factors probably underlie diabetic cardiomyopathy: severe coronary atherosclerosis, prolonged hypertension, chronic hyperglycemia, microvascular disease, glycosylation of myocardial proteins, and autonomic neuropathy. Improved glycemic control, better control of hypertension, and prevention of atherosclerosis with cholesterol-lowering therapy may prevent or mitigate diabetic cardiomyopathy. An early clinical trial³⁸ suggested that sulfonyl ureas used for control of hyperglycemia are cardiotoxic and may exacerbate diabetic cardiomyopathy. This side effect, however, was not confirmed in a recent large clinical trial.³⁹

Stroke
Mortality from stroke is increased almost 3-fold when patients with diabetes are matched to those without diabetes.⁴⁰ The most common site of cerebrovascular disease in patients with diabetes is occlusion of small paramedial penetrating arteries.⁴¹ Diabetes also increases the likelihood of severe carotid atherosclerosis.^{42 43} Patients with diabetes, moreover, are likely to suffer irreversible brain damage with carotid emboli that otherwise would produce only transient ischemic attacks in persons without diabetes. Approximately 13% of patients with diabetes >65 years old have had a stroke.⁴⁴

Renal Disease
Renal disease is a common and often severe complication of diabetes.⁴⁵ Approximately 35% of patients with type 1 diabetes of 18 years' duration will have signs of diabetic renal involvement.⁴⁶ Up to 35% of new patients beginning dialysis therapy have type 2 diabetes.⁴⁷ End-stage renal disease (ESRD) appears to be especially common among Hispanics, blacks, and Native Americans with diabetes.^{48 49 50 51 52} For patients with diabetes who are on renal dialysis, mortality rates probably exceed 20% per year.⁴⁷ When diabetes is present, CVD is the leading cause of death among patients with ESRD.^{53 54 55}

	Covariate Risk Factors

Top Introduction Clinical Presentations of... Scope of the Problem Diabetes as a Major... Diabetes and Specific CVD Covariate Risk Factors Risk Assessment in the... Clinical Evaluation Cardiovascular Clinical... Primary Prevention Implications for Treatment of... References

 
Prospective studies^{22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40} indicate that all of the major cardiovascular risk factors—cigarette smoking, hypertension, and high serum cholesterol—continue to act as independent contributors to CVD in patients with diabetes. As already mentioned, clustering of metabolic risk factors, called the metabolic syndrome, occurs commonly in type 2 diabetes.⁵⁶ The onset of hyperglycemia in patients with the metabolic syndrome appears to accelerate atherogenesis, possibly by enhanced formation of glycosylated proteins and advanced glycation products^{57 58} and/or by increasing endothelial dysfunction.⁵⁹ These direct consequences of hyperglycemia probably contribute to the microvascular disease underlying nephropathy and retinopathy, and they may promote macrovascular disease as well.

Predisposing Risk Factors
Several predisposing factors simultaneously affect the development of CVD and diabetes mellitus. Among these concomitant factors are obesity, physical inactivity, heredity, sex, and advancing age. The mechanisms whereby they predispose to chronic diseases are complex and often overlapping. To some extent, these predisposing factors exacerbate the major risk factors: dyslipidemia, hypertension, and glucose tolerance; and they may cause CVD and diabetes mellitus through other pathways as well. To a large extent, both CVD and diabetes must be prevented through control of the predisposing risk factors. Modification of life habits is at the heart of the public health strategy for prevention of CVD and diabetes mellitus. High priorities are the prevention (or treatment) of obesity and promotion of physical activity. Drug therapy nonetheless may be required to control the metabolic risk factors, particularly when they arise from genetic aberration and aging. Effective drugs are currently available for treatment of hypertension and dyslipidemia. Hypoglycemic agents also are available for treatment of type 2 diabetes, but new pharmacological strategies are under investigation for more effective treatment and prevention.

Insulin Resistance and the Metabolic Syndrome
Most patients with type 2 diabetes have insulin resistance. Indeed, insulin resistance seems to predispose to both CVD and diabetes.⁶⁰ Research suggests that insulin resistance is a multisystem disorder that induces multiple metabolic alterations. Factors that contribute to insulin resistance are genetics,⁶¹ obesity,⁶² physical inactivity,⁶³ and advancing age.⁶⁴ Patients with insulin resistance often have abdominal obesity.⁶⁵ Metabolic risk factors that occur commonly in patients with insulin resistance are atherogenic dyslipidemia, hypertension, glucose intolerance, and a prothrombotic state.⁶⁰ Each of these risk factors can be reviewed briefly.

Atherogenic Dyslipidemia
Atherogenic dyslipidemia is characterized by 3 lipoprotein abnormalities: elevated very-low-density lipoproteins (VLDL), small LDL particles, and low high-density-lipoprotein (HDL) cholesterol (the lipid triad). The lipid triad occurs frequently in patients with premature CHD and appears to be an atherogenic lipoprotein phenotype independent of elevated LDL cholesterol.^{66 67 68 69} Most patients with atherogenic dyslipidemia are insulin resistant.^{69 70 71} Atherogenic dyslipidemia in diabetic patients often is called diabetic dyslipidemia. Many patients with atherogenic dyslipidemia also have an elevated serum total apolipoprotein B.⁷² Growing evidence suggests that all of the components of the lipid triad are independently atherogenic. Together they represent a set of lipoprotein abnormalities besides elevated LDL cholesterol that promote atherosclerosis.

Hypertension
Hypertension is a well-established major risk factor for CVD.²² It increases risk for both CHD and stroke and contributes to diabetic nephropathy.⁷³ Several investigators^{74 75} report a positive association between insulin resistance and hypertension; this finding suggests that elevated blood pressure deserves to be listed among the components of the metabolic syndrome. Hypertension nonetheless is a multifactorial disorder, and the mechanistic connections between insulin resistance and hypertension are largely conjectural; even so, evidence for a causal link is growing.⁷⁶ When hypertension coexists with overt diabetes, which it commonly does, the risk for CVD, including nephropathy, is doubly increased.

Elevated Plasma Glucose
For several years after onset of insulin resistance, fasting and postprandial glucose levels typically are normal. During this period, pancreatic ß-cells are able to increase insulin secretion in response to insulin resistance and thereby maintain normal plasma glucose levels. In some people, however, insulin secretion declines with aging, and elevated glucose concentrations appear. The first abnormality in plasma glucose in patients with insulin resistance is IFG (or impaired glucose tolerance).⁹ The presence of IFG usually accompanies long-standing insulin resistance. It is currently estimated that 13.4 million adults, 7.0% of the US population, have IFG.¹⁴ Many prospective studies^{77 78} show that IFG (or impaired glucose tolerance) is a risk factor for CVD; the degree of independence as a risk factor, however, is uncertain, because IGF commonly coexists with other components of the metabolic syndrome.¹¹ A patient with IFG nonetheless must be considered at risk for both CVD and type 2 diabetes. As already indicated, once categorical hyperglycemia develops, it counts as an independent risk factor for CVD.²²

Prothrombotic State
A newly recognized component of the metabolic syndrome is a prothrombotic state.⁷⁶ Patients with insulin resistance frequently manifest several alterations in coagulation mechanisms that predispose them to arterial thrombosis. These alterations include increased fibrinogen levels,⁷⁹ increased plasminogen activator inhibitor-1,⁸⁰ and various platelet abnormalities.⁸¹

LDL Cholesterol and Atherogenesis in Diabetic Patients
An elevated concentration of serum LDL cholesterol is a major risk factor for CHD.⁸² In fact, some elevation of LDL cholesterol appears to be necessary for the initiation and progression of atherosclerosis. In populations having very low LDL cholesterol levels, clinical CHD is relatively rare, even when other risk factors—hypertension, cigarette smoking, and diabetes—are common.⁸³ In contrast, severe elevations in LDL cholesterol can produce full-blown atherosclerosis and premature CHD in the complete absence of other risk factors.⁸⁴

The view has been expressed that most patients with diabetes do not have an elevated serum LDL cholesterol; if not, a high LDL serum cholesterol would not be a common risk factor in patients with diabetes. It is true that most patients who have diabetes do not have marked elevations of LDL cholesterol, but these patients nonetheless carry high enough levels to support the development of atherosclerosis.⁸⁵ A role for LDL in hyperglycemic patients became apparent in recent clinical trials, eg, the Scandinavian Simvastatin Survival Study (4S),^{86 87} the Cholesterol and Recurrent Events (CARE) trial,^{88 89} and the Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID).⁹⁰ In all of these trials, aggressive LDL-lowering therapy reduced recurrent CHD events in patients with diabetes.

Cigarette Smoking
Cigarette smoking is a leading risk factor for CVD. Patients with diabetes who are smokers are doubly at risk. Unfortunately, many patients continue to smoke despite having diabetes; for these patients, the benefits that can be derived from modifying other risk factors are mitigated.

Diabetic Nephropathy
Diabetic nephropathy can be divided into 4 phases: microalbuminuria, macroalbuminuria, the nephrotic syndrome, and chronic renal failure.⁴⁵ Microalbuminuria (urine albumin 30 to 300 mg/d or <300 mg/g creatinine) is the first clinical sign of diabetic damage to the kidney.^{91 92} Not only is microalbuminuria a harbinger of progressive kidney damage, but its presence also reflects a higher risk for CVD.^{92 93 94 95} Macroalbuminuria (urine albumin >300 mg/d or >300 mg/g creatinine) usually denotes significant diabetic nephropathy and will be followed by a decline in glomerular filtration rate (GFR). The majority of patients with diabetes who have macroalbuminuria also have hypertension^{96 97} ; in these patients, control of hypertension slows the decline in GFR.^{98 99 100} Some patients with diabetes develop the nephrotic syndrome (urine protein >3 g/d); diabetic dyslipidemia in such patients often is compounded by nephrotic dyslipidemia, most notably by higher cholesterol levels. The nephrotic syndrome usually heralds progressive renal insufficiency; thereafter, ESRD ensues and dialysis and/or transplantation become necessary to sustain life.

	Risk Assessment in the Diabetic Patient

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Risk assessment must take into account the major risk factors (cigarette smoking, elevated blood pressure, abnormal serum lipids and lipoproteins, and hyperglycemia) and predisposing risk factors (excess body weight and abdominal obesity, physical inactivity, and family history of CVD). Identification of risk factors is a major first step for developing a plan for risk reduction in persons with diabetes. Specific steps in the evaluation of the major risk factors in such persons are presented in Table 1. These steps include a thorough medical history, careful physical examination, and appropriate laboratory measurements. Specialized testing may be particularly useful, eg, 24-hour monitoring of ambulatory blood pressure by automated techniques. Lipoprotein analysis should draw a clear distinction between elevated LDL cholesterol concentrations and atherogenic dyslipidemia (or diabetic dyslipidemia) as manifested by elevated triglycerides and small LDL and low HDL cholesterol levels. Even borderline-high-risk LDL cholesterol levels (130 to 159 mg/dL) are of concern in patients with diabetes and call for aggressive intervention. The quality of glycemic control can best be assessed by periodic measurement of hemoglobin A1c. Furthermore, because hyperglycemia per se confers increased risk for CVD, the presence of other risk factors—smoking, hypertension, even borderline-high-risk LDL cholesterol, and atherogenic dyslipidemia—signifies enhanced risk and signals the need for more aggressive intervention on all risk factors.

View this table: [in this window] [in a new window]   Table 1. Evaluation of Major Risk Factors in Diabetic Patients

Risk assessment in the diabetic patient is not complete until predisposing risk factors—obesity, physical inactivity, and family history of premature CVD—have been evaluated (Table 2). Identification of predisposing risk factors will provide insight into the causation of the major risk factors. The finding of abdominal obesity, as evidenced by an increased waist circumference, usually indicates the presence of insulin resistance. A careful assessment of the status of the predisposing risk factor sets the stage for therapeutic modification of life habits. A genetic basis for risk, as revealed by a positive family history of CVD or diabetes, may point to the need for pharmacological control of risk factors. Moreover, a positive family history often uncovers family members who also need risk-factor intervention.

View this table: [in this window] [in a new window]   Table 2. Evaluation of Predisposing Risk Factors in Diabetic Patients

	Clinical Evaluation

Top Introduction Clinical Presentations of... Scope of the Problem Diabetes as a Major... Diabetes and Specific CVD Covariate Risk Factors Risk Assessment in the... Clinical Evaluation Cardiovascular Clinical... Primary Prevention Implications for Treatment of... References

 
Detection of Clinical and Subclinical CVD
Prospective studies¹⁰¹ document an increased likelihood of sudden cardiac death and unrecognized myocardial infarctions in patients with diabetes. Moreover, acute ischemic syndromes, peripheral arterial disease, and advanced CVD complications occur more commonly in patients with diabetes than in those without.¹⁰¹ Because the typical cardiac symptoms often are masked in patients with diabetes, the diagnosis of myocardial infarction commonly is missed or delayed. Effective strategies for earlier detection of clinical CVD could reduce morbidity and mortality in patients with diabetes. In addition, detection of subclinical atherosclerosis and early clinical manifestation of CVD could lead to more effective primary prevention in some patients with diabetes.

Table 3 outlines a general approach to the detection of clinical and subclinical CVD in the hyperglycemic patient. Stress testing for myocardial ischemia and dysfunction should be performed in accord with general American College of Cardiology (ACC)/AHA guidelines¹⁰² ; Table 3 lists further special considerations for exercise testing in patients with diabetes. Noninvasive evaluation of cardiac function in hyperglycemic patients suspected of having myocardial dysfunction may be a useful guide to cardiovascular management in some of these patients. Many patients with diabetes suffer from an autonomic dysfunction that impairs quality of life and predisposes to life-threatening cardiovascular complications. Finally, the finding of subclinical CVD signals the need for institution of more aggressive preventive measures.

View this table: [in this window] [in a new window]   Table 3. Detection of Clinical and Subclinical Cardiovascular Disease in the Diabetic Patient

Evaluation of Renal Status
Chronic renal failure is a major clinical outcome in patients with diabetes. It is more likely to develop in type 1 diabetes than in type 2 diabetes. However, the high prevalence of type 2 diabetes makes it a major cause of ESRD. The renal status of patients with diabetes therefore must be appropriately monitored so that effective intervention can be introduced early in the course of renal disease. Table 4 outlines the steps in evaluation. Testing for urine albumin and protein is the first step. Microalbuminuria is indicative of early diabetic nephropathy. In patients with type 1 diabetes, it is a harbinger of ongoing renal damage; in type 2 diabetes, it signifies enhanced risk for CVD. Macroalbuminuria and/or nephrotic-range proteinuria predicts a decline in renal function. Patients with macroalbuminuria should be referred to a nephrologist who can rule out another kidney disease and who can help to plan a strategy for preventing progression to ESRD. This strategy should include aggressive management of hypertension to blood pressure levels of <130/85 mm Hg. Although the serum creatinine is not a sensitive indicator of the degree of loss of GFR, a rising serum creatinine plotted as changes in the reciprocal of serum creatinine versus time provides a means of determining the rate of decline in renal function. Direct measurement of GFR is the most reliable estimate of the amount of residual kidney function but is more expensive and technically demanding.

View this table: [in this window] [in a new window]   Table 4. Evaluation of Renal Status

	Cardiovascular Clinical Management

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Medical (Noninvasive) Management of Diabetic Patients With Clinical CVD
Compelling evidence, including data from recent clinical trials, demonstrates that comprehensive medical intervention in patients with established atherosclerotic CVD has thefollowing benefits: it extends overall survival; improves quality of life; decreases the need for intervention procedures, such as angioplasty and coronary artery bypass graft surgery; and reduces the incidence of subsequent myocardial infarction.¹⁰³ In many patients with CHD, aggressive risk reduction with medical therapy will delay or eliminate the need for revascularization procedures. Treatment of risk factors in patients with established CHD or other clinical atherosclerotic disease has been called secondary prevention. Although the number of patients with diabetes included in clinical trials has been limited, the available results suggest that these patients respond to secondary prevention interventions at least as well as those without diabetes.^{86 87 88 89 90} Consequently, the general guidelines for noninvasive, medical management in secondary prevention can be applied when patients with diabetes have clinical atherosclerotic CVD. Table 5 summarizes the AHA/ACC guide¹⁰³ to comprehensive risk reduction in patients with clinical coronary and other vascular disease, as modified for CVD patients with diabetes.

View this table: [in this window] [in a new window]   Table 5.

A few general comments can be made about application of these guidelines to patients with diabetes. Because cigarette smoking remains a powerful risk factor in patients with diabetes, a major effort must be made to overcome the smoking habit. The AHA has recently published practical guidelines for assisting patients in smoking cessation.¹⁰⁴ For lipid management, the primary goal of therapy is to reduce LDL-cholesterol levels to 100 mg/dL.¹⁰³ This goal should be achieved by addition of drug therapy (when necessary) to maximal dietary therapy. Statins are first-line therapy to achieve an LDL cholesterol of 100 mg/dL. When triglycerides remain >200 mg/dL in patients receiving statin therapy, consideration should be given to adding a fibrate to achieve the secondary goal of lipid management, ie, a triglyceride <200 mg/dL. Although nicotinic acid effectively lowers triglycerides and raises HDL levels in patients with type 2 diabetes, its tendency to worsen hyperglycemia causes it to be relatively contraindicated. The goal of blood pressure control is to reduce blood pressure to <135/85 mm Hg in hypertensive patients¹⁰⁵ ; this goal often will require antihypertensive drug therapy.

Treatment of hyperglycemia is stepwise and typically dependent on duration of disease. To prevent microangiopathy, neuropathy, and perhaps macrovascular disease, a prudent therapeutic goal is to reduce the glycohemoglobin to 1% above the upper limit of normal.^{39 106} Weight loss and increased exercise are first-line therapy for reducing hyperglycemia. If hyperglycemia persists, a sulfonylurea or metformin can be used next. The recent UK Prospective Diabetes Study³⁹ revealed the safety and efficacy of sulfonylureas in control of hyperglycemia in diabetic patients. Metformin also proved efficacious, although an apparent increase in death rates on the combination of metformin and sulfonylureas calls for more study on the safety of this combination.¹⁰⁷

Another promising group of agents for treatment of type 2 diabetes includes the thiazolidenediones. These agents lower glucose levels by reducing insulin resistance. The first drug in this class to be approved for clinical use was troglitazone. This agent is approved for use in combination with insulin therapy to improve glycemic control. Unfortunately, troglitazone produces rare but severe liver toxicity^{108 109 110} ; the possibility of this adverse reaction requires close monitoring of patients. Nonetheless, despite its potential hepatotoxicity, troglitazone is currently being widely used to treat hyperglycemia. New drugs of the same class, rosiglitazone and pioglitazone, may have less potential hepatotoxicity. A different type of drug available for glucose control is acarbose; this agent partially blocks glucose absorption. In patients who fail to achieve glucose control and near-normal hemoglobin A1c levels by changes in life habits and oral hypoglycemic agents, insulin should be initiated.

Other risk-reduction strategies in patients with diabetes deserve attention equal to that given glucose control. Patients with type 2 diabetes should increase physical activity and eliminate excess body weight; both may be facilitated with the help of professional guidance. Antiplatelet agents have become almost routine in patients with atherosclerotic CVD, and their use can be extended to patients with diabetes who have established atherosclerotic disease. ß-Blockers reduce cardiovascular mortality after myocardial infarction. They may be particularly effective in patients with diabetes, who are at risk for symptomatic ischemic episodes secondary to increased sympathetic activity.¹¹¹ ß-Blockers are often mentioned as being contraindicated for patients with diabetes because of their blocking of hypoglycemic symptoms in the presence of a hypoglycemic regimen. Clinicians should be aware of this potential danger, although this side effect need not preclude use of ß-blockers when CHD patients have diabetes. Angiotensin-converting enzyme (ACE) inhibitors are widely prescribed in the post–myocardial infarction period to favorably influence myocardial remodeling and fibrosis, and they should be continued indefinitely in all patients with reduced left ventricular ejection fraction or symptoms of heart failure. Unfortunately, limited data are available on use of estrogen replacement therapy in postmenopausal women with diabetes; a recent clinical trial calls into question its putative benefit in postmenopausal, nondiabetic women with established CHD.¹¹²

Management of Diabetic Nephropathy
More than one strategy has been shown to slow the progression of nephropathy in patients with diabetes. A general approach is outlined in Table 6. Specific interventions include control of hyperglycemia, treatment of hypertension (particularly by use of ACE inhibitors), sodium restriction, and dietary protein restriction. Treatment of hypertension with ACE inhibitors can retard the progression of diabetic nephropathy. ACE inhibitors in fact may have favorable effects on nephropathy even in the absence of hypertension, although it is uncertain whether normotensive patients should use them clinically for this purpose.

View this table: [in this window] [in a new window]   Table 6. Management of Diabetic Nephropathy

Invasive Management of Coronary Artery Disease
Recent studies^{113 114 115 116} indicate that coronary angioplasty is less efficacious for patients with diabetes than for those without; these reports further reveal that coronary artery bypass surgery is the preferred therapy in patients with diabetes when invasive management is required. Most of the benefit from coronary bypass grafting seems to result from use of the internal mammary artery. Thus, at present, the preferred invasive approach for coronary revascularization in patients with diabetes is use of internal mammary arteries with bypass grafting. Extensive data are not yet available with use of coronary stents in patients with diabetes, but regardless, bypass grafting seems to be preferred.

	Primary Prevention

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Type 2 diabetes can be viewed as the end product of years of metabolic stress accompanying a state of insulin resistance. It seems that in patients with insulin resistance, the "clock starts ticking" for acceleration of atherogenesis long before the onset of hyperglycemia.¹¹ Thus, early detection of the risk factors associated with the metabolic syndrome is needed for institution of appropriate primary prevention measures in patients at risk for diabetes. Clinical evidence of insulin resistance includes abdominal obesity (or borderline abdominal obesity), high-normal blood pressure (or mild hypertension), high-normal triglycerides (150 to 250 mg/dL), reduced HDL cholesterol (<40 mg/dL in men; <50 mg/dL in women), borderline high-risk LDL cholesterol (130 to 159 mg/dL), and in some patients, IFG (110 to 126 mg/dL). The detection of IFG seems particularly significant; it usually signifies long-standing insulin resistance and is a strong risk factor for type 2 diabetes. The AHA has recently published a guide to primary prevention of CVD.¹¹⁷ This guide integrates well with efforts for early detection of the metabolic syndrome, and it recommends interventions to reduce the risk for CVD for patients without established CVD. If these guidelines are followed, they probably would delay the onset of type 2 diabetes as well as reducing risk for CVD. The American Diabetes Association likewise has recently updated its recommendations for management and risk reduction in patients with diabetes.¹¹⁸

Primary Prevention of CVD in Diabetic Patients
The guide outlined for primary prevention of CVD is expanded to include diabetic patients in Table 7. Goals for smoking cessation, blood pressure control, physical activity, and weight management are the same as for nondiabetic patients. However, more aggressive management of cholesterol and other lipids is indicated for diabetic patients, as discussed by the recent American Diabetes Association reports.^{118 119 120} Treatment of hyperglycemia should follow the same regimen as discussed under secondary prevention.

View this table: [in this window] [in a new window]   Table 7.

	Implications for Treatment of Patients With Type I Diabetes

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The predominant risk factor for CHD in patients with type 1 diabetes is duration of disease. Nonetheless, smoking, hypertension, renal disease (macroalbuminuria and renal insufficiency), and dyslipidemia remain important. Effective treatment of hyperglycemia reduces microvascular complications of type 1 diabetes.¹⁰⁶ It also may reduce risk for macrovascular disease.¹⁰⁶ Modification of other CVD risk factors almost certainly will reduce risk. This would include not only tobacco avoidance but also maintenance of blood pressures <130/85 mm Hg, screening for microalbuminuria, and reducing triglycerides to at least <200 mg/dL and perhaps lower. The optimal LDL-cholesterol level in patients with diabetes is 100 mg/dL; however, use of cholesterol-lowering drugs to achieve this goal in younger patients with type 1 diabetes may not be appropriate. Aspirin also can be administered in patients who have long-standing type 1 diabetes and in whom goals for glycohemoglobin are not achieved.

	Footnotes

 
This statement was approved by the American Heart Association Science Advisory and Coordinating Committee in April 1999. A single reprint is available by calling 800-242-8721 (US only) or writing the American Heart Association, Public Information, 7272 Greenville Ave, Dallas, TX 75231-4596. Ask for reprint No. 71-0175. To purchase additional reprints: up to 999 copies, call 800-611-6083 (US only) or fax 413-665-2671; 1000 or more copies, call 214-706-1466, fax 214-691-6342, or

	References

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1. Gerick JE. The genetic basis of type 2 diabetes mellitus: impaired insulin secretion versus impaired insulin sensitivity. Endocr Rev. 1998;19:491–503.[Abstract/Free Full Text]
   
2. Chisholm DJ, Campbell LV, Kraegen EW. Pathogenesis of the insulin resistance syndrome (syndrome X). Clin Exp Pharmacol Physiol. 1997;24:782–784.[Medline] [Order article via Infotrieve]
   
3. Muller DC, Elahi D, Tobin JD, Andres R. The effect of age on insulin resistance and secretion: a review. Semin Nephrol. 1996;16:289–298.[Medline] [Order article via Infotrieve]
   
4. Dechenes CJ, Verchere CB, Andrikopoulos S, Kahn SE. Human aging is associated with parallel reductions in insulin and amylin release. Am J Physiol. 1998;275:E785–E791.[Abstract/Free Full Text]
   
5. Pimenta W, Korytkowski M, Mitrakou A, Jenssen T, Yki-Jarvinen H, Evron W, Dailey G, Gerich J. Pancreatic beta-cell dysfunction as the primary genetic lesion in NIDDM: evidence from studies in normal glucose-tolerant individuals with a first-degree NIDDM relative. JAMA. 1995;273:1855–1861.[Abstract]
   
6. Humphriss DB, Stewart MW, Berrish TS, Barriocanal LA, Trajano LR, Ashworth LA, Brown MD, Miller M, Avery PJ, Alberti KG, Walker M. Multiple metabolic abnormalities in normal glucose tolerant relatives of NIDDM families. Diabetologia. 1997;40:1185–1190.[Medline] [Order article via Infotrieve]
   
7. Hopkins PN, Hunt SC, Wu LL, Williams GH, Williams RR. Hypertension, dyslipidemia, and insulin resistance: links in a chain or spokes on a wheel? Curr Opin Lipidol. 1996;7:241–253.[Medline] [Order article via Infotrieve]
   
8. Gray RS, Fabsitz RR, Cowan LD, Lee ET, Howard BV, Savage PJ. Risk factor clustering in the insulin resistance syndrome: the Strong Heart Study. Am J Epidemiol. 1998;148:869–878.[Abstract/Free Full Text]
   
9. The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care. 1997;20:1183–1202.[Medline] [Order article via Infotrieve]
   
10. Stern MP. Impaired glucose tolerance: risk factor or diagnostic category. In: LeRoith D, Taylor SI, Olefsky JM, eds. Diabetes Mellitus: A Fundamental and Clinical Text. Philadelphia, Pa: Lippincott-Raven Publishers; 1996:467–474.
    
11. 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.[Abstract]
    
12. Unger RH, Foster DW. Diabetes mellitus. In: Wilson JD, Foster DW, Kronenberg HM, Larsen PR, eds. Williams Textbook of Endocrinology. Philadelphia, Pa: WB Saunders Co; 1998:973–1059.
    
13. Lloyd CE, Kuller LH, Ellis D, Becker DJ, Wing RR, Orchard TJ. Coronary artery disease in IDDM: gender differences in risk factors but not risk. Arterioscler Thromb Vasc Biol. 1996;16:720–726.[Abstract/Free Full Text]
    
14. Diabetes Statistics. National Diabetes Information Clearinghouse. Bethesda, Md: National Institute of Diabetes and Digestive and Kidney Diseases, NIH publication 99-3926. 1999.
    
15. Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults: the Evidence Report. Bethesda, Md: National Institutes of Health, National Heart, Lung, and Blood Institute; 1998.
    
16. US Department of Health and Human Services. Physical Activity and Health: A Report of the Surgeon General. Atlanta, Ga: US Department of Health and Human Services; Centers for Disease Control and Prevention; National Center for Chronic Disease Prevention and Health Promotion; 1996.
    
17. Carter JS, Pugh JA, Monterrosa A. Non-insulin-dependent diabetes mellitus in minorities in the United States. Ann Intern Med. 1996;125:221–232.[Abstract/Free Full Text]
    
18. Lindeman RD, Romero LJ, Hundley R, Allen AS, Liang HC, Baumgartner RN, Koehler KM, Schade DS, Garry PJ. Prevalences of type 2 diabetes, the insulin resistance syndrome, and coronary heart disease in an elderly, biethnic population. Diabetes Care. 1998;21:959–966.[Abstract]
    
19. Cappuccio FP, Cook DG, Atkinson RW, Strazzullo P. Prevalence, detection, and management of cardiovascular risk factors in different ethnic groups in south London. Heart. 1997;78:555–563.[Abstract/Free Full Text]
    
20. Prevalence of diagnosed diabetes among American Indians/Alaskan Natives—United States, 1996. MMWR Morb Mortal Wkly Rep. 1998;47:901–904.[Medline] [Order article via Infotrieve]
    
21. Wilson PW, D'Agostino RB, Levy D, Belanger AM, Silbershatz H, Kannel WB. Prediction of coronary heart disease using risk factor categories. Circulation. 1998;97:1837–1847.[Abstract/Free Full Text]
    
22. Wilson PW. Diabetes mellitus and coronary heart disease. Am J Kidney Dis. 1998;32:S89–S100.[Medline] [Order article via Infotrieve]
    
23. McGill HC Jr, McMahan CA. Determinants of atherosclerosis in the young: Pathobiological Determinants of Atherosclerosis in Youth (PDAY) Research Group. Am J Cardiol. 1998;82:30T–36T.[Medline] [Order article via Infotrieve]
    
24. Brezinka V, Padmos I. Coronary heart disease risk factors in women. Eur Heart J. 1994;15:1571–1584.[Abstract/Free Full Text]
    
25. Geiss LS, Herman WH, Smith PJ, National Diabetes Data Group. Diabetes in America. Bethesda, Md: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 1995:233–257.
    
26. Stone PH, Muller JE, Hartwell T, York BJ, Rutherford JD, Parker CB, Turi ZG, Strauss HW, Willerson JT, Robertson T, et al, the MILIS Study Group. The effect of diabetes mellitus on prognosis and serial left ventricular function after acute myocardial infarction: contribution of both coronary disease and diastolic left ventricular dysfunction to the adverse prognosis. J Am Coll Cardiol. 1989;14:49–57.[Abstract]
    
27. Singer DE, Moulton AW, Nathan DM. Diabetic myocardial infarction: interaction of diabetes with other preinfarction risk factors. Diabetes. 1989;38:350–357.[Abstract]
    
28. Smith JW, Marcus FI, Serokman R. Prognosis of patients with diabetes mellitus after acute myocardial infarction. Am J Cardiol. 1984;54:718–721.[Medline] [Order article via Infotrieve]
    
29. Wingard DL, Barrett-Connor EL, Scheidt-Nave C, McPhillips JB. Prevalence of cardiovascular and renal complications in older adults with normal or impaired glucose tolerance or NIDDM: a population-based study. Diabetes Care. 1993;16:1022–1025.[Abstract]
    
30. Rubler S, Dlugash J, Yuceoglu YZ, Kumral T, Branwood AW, Grishman A. New type of cardiomyopathy associated with diabetic glomerulosclerosis. Am J Cardiol. 1972;30:595–602.[Medline] [Order article via Infotrieve]
    
31. Regan TJ, Lyons MM, Ahmed SS, Levinson GE, Oldewurtel HA, Ahmad MR, Haider B. Evidence of cardiomyopathy in familial diabetes mellitus. J Clin Invest. 1977;60:884–899.
    
32. Regan TJ. Congestive heart failure in the diabetic. Annu Rev Med. 1983;34:161–168.[Medline] [Order article via Infotrieve]
    
33. Ettinger PO, Regan TJ. Cardiac disease in diabetes. Postgrad Med. 1989;85:229–232.
    
34. van Hoeven KH, Factor SM. A comparison of the pathological spectrum of hypertensive, diabetic, and hypertensive-diabetic heart disease. Circulation. 1990;82:848–855.[Abstract/Free Full Text]
    
35. Gotzsche O, Darwish A, Gotzsche L, Hansen LP, Sorensen KE. Incipient cardiomyopathy in young insulin-dependent diabetic patients: a seven-year prospective Doppler echocardiographic study. Diabet Med. 1996;13:834–840.[Medline] [Order article via Infotrieve]
    
36. Spector KS. Diabetic cardiomyopathy. Clin Cardiol. 1998;21:885–887.[Medline] [Order article via Infotrieve]
    
37. Mahgoub MA, Abd-Elfattah AS. Diabetes mellitus and cardiac function. Mol Cell Biochem. 1998;180:59–64.[Medline] [Order article via Infotrieve]
    
38. Klimt CR, Knatterud GI, Meinert CL, Prout TE, University Group Diabetes Program. A study of the effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes, II: mortality results. Diabetes. 1970;19(suppl):789–830.
    
39. 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.[Medline] [Order article via Infotrieve]
    
40. Stamler J, Vaccaro O, Neaton JD, Wentworth D. Diabetes, other risk factors, and 12-year cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial (MRFIT). Diabetes Care. 1993;16:434–444.[Abstract]
    
41. Bell DSH. Stroke in the diabetic patient. Diabetes Care. 1994;17:213–219.[Abstract]
    
42. Folsom AR, Eckfeldt JH, Weitzman S, Ma J, Chambless LE, Barnes RW, Cram KB, Hutchinson RG, Atherosclerosis Risk in Communities Study Investigators. Relation of carotid artery wall thickness in diabetes mellitus, fasting glucose and insulin, body size, and physical activity. Stroke. 1994;25:66–73.[Abstract]
    
43. O'Leary DH, Polak JF, Kronmal RA, Kittner SJ, Bond MG, Wolfson SK Jr, Bommer W, Price TR, Gardin JM, Savage PJ. Distribution and correlates of sonographically detected carotid artery disease in the Cardiovascular Health Study. Stroke. 1992;23:1752–1760.[Abstract/Free Full Text]
    
44. Kuller LH, National Diabetes Data Group. Stroke and diabetes. In: Diabetes in America. Bethesda, Md: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 1995:449–456.
    
45. Nelson RG, Knowler WC, Pettitt JD, Bennett PH, National Diabetes Data Group. Kidney diseases in diabetes. In: Diabetes in America. Bethesda, Md: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 1995:349–400.
    
46. Mogensen CE, Christensen CK, Vittinghus E. The stages of diabetic renal disease: with emphasis on the stage of incipient diabetic nephropathy. Diabetes. 1983;32:64–78.
    
47. US Renal Data System. USRDS 1994 Annual Data Report. Bethesda, Md: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 1994.
    
48. Cowie CC, Port FK, Wolfe RA, Savage PJ, Moll PP, Hawthorne VM. Disparities in incidence of diabetic end-stage renal disease according to race and types of diabetes. N Engl J Med. 1989;321:1074–1079.[Abstract]
    
49. Rostand SG, Kirk KA, Rutsky EA, Pate BA. Racial differences in the incidence of treatment for end-stage renal disease. N Engl J Med. 1982;306:1276–1279.[Medline] [Order article via Infotrieve]
    
50. Stephens GW, Gillaspy JA, Clyne D, Mejia A, Pollak VE. Racial differences in the incidence of end-stage renal disease in types I and II diabetes mellitus. Am J Kidney Dis. 1990;15:562–567.[Medline] [Order article via Infotrieve]
    
51. Lopes AA, Port FK, James SA, Agodoa L. The excess risk of treated end-stage renal disease in blacks in the United States. J Am Soc Nephrol. 1993;3:1961–1971.[Abstract]
    
52. Nelson RG, Pettitt DJ, Carraher MJ, Baird HR, Knowler WC. Effect of proteinuria on mortality in NIDDM. Diabetes. 1988;37:1499–1504.[Abstract]
    
53. McMillan MA, Briggs JD, Junor BJ. Outcome of renal replacement treatment in patients with diabetes mellitus. BMJ. 1990;301:540–544.
    
54. Hirschl MM, Heinz G, Sunder-Plassmann G, Derfler K. Renal replacement therapy in type 2 diabetic patients: 10 years' experience. Am J Kidney Dis. 1992;20:564–568.[Medline] [Order article via Infotrieve]
    
55. Rischen-Vos J, van der Woude FJ, Tegzess AM, Zwinderman AH, Gooszen HC, van den Akker PJ, van Es LA. Increased morbidity and mortality in patients with diabetes mellitus after kidney transplantation as compared with non-diabetic patients. Nephrol Dial Transplant. 1992;7:433–437.[Abstract/Free Full Text]
    
56. ADA Consensus Panel. Role of cardiovascular risk factors in prevention and treatment of macrovascular disease in diabetes: American Diabetes Association. Diabetes Care. 1989;12:573–579.[Medline] [Order article via Infotrieve]
    
57. Brownlee M, Cerami A, Vlassara H. Advanced glycosylation end products in tissue and the biochemical basis of diabetic complications. N Engl J Med. 1988;318:1315–1321.[Medline] [Order article via Infotrieve]
    
58. Hammes H-P, Brownlee M. Advanced glycation end products and pathogenesis of diabetic complications. In: LeRoith D, Taylor SI, Olefsky JM, eds. Diabetes Mellitus: A Fundamental and Clinical Text. Philadelphia, Pa: Lippincott-Raven Publishers: 1996:810–815.
    
59. Nadler JL, Winer L. Free radicals, nitric oxide, and diabetic complications. In: LeRoith D, Taylor SI, Olefsky JM, eds. Diabetes Mellitus: A Fundamental and Clinical Text. Philadelphia, Pa: Lippincott-Raven Publishers; 1996:840–847.
    
60. 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, Pa: Lippincott-Raven Publishers; 1996:509–519.