Practice Guidelines

AHA Examines Cardiovascular Problems in Diabetes



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Am Fam Physician. 2000 Jan 15;61(2):561-567.

The American Heart Association (AHA) has issued recommendations for interventions to reduce the risk of cardiovascular complications in patients with diabetes mellitus. Developed by the AHA Science Advisory and Coordinating Committee, the AHA scientific statement appears in the September 7, 1999 issue of Circulation. It is also available on the Circulation Web site (http://www.circulationaha.org). In addition, single reprints may be obtained by calling 800-242-8721 or writing the American Heart Association, Public Information, 7272 Greenville Ave., Dallas, TX 75231-4596. The following summarizes the recommendations for reducing the risk of cardiovascular disease and its complications in patients who have diabetes.

Predisposing Risk Factors for Cardiovascular Disease

The AHA scientific statement begins with the assertion that “from the point of view of cardiovascular medicine, it may be appropriate to say ‘diabetes is a cardiovascular disease.’” The report notes that the combination of insulin resistance, dyslipidemia, hypertension and prothrombotic factors often precedes the development of type 2 diabetes (formerly known as non–insulin-dependent diabetes) by many years. This constellation is referred to in the report as the metabolic syndrome.

According to the AHA report, myocardial ischemia from coronary atherosclerosis frequently is asymptomatic in patients with diabetes. As a result, atherosclerosis has often progressed to involve multiple vessels before ischemic symptoms occur and before treatment is initiated. In addition, the poor prognosis in patients with diabetes and ischemic heart disease seems to relate to an enhanced myocardial dysfunction that leads to accelerated heart failure. Factors that probably underlie diabetic cardiomyopathy include severe coronary atherosclerosis, prolonged hypertension, chronic hyperglycemia, microvascular disease, glycosylation of myocardial proteins and autonomic neuropathy. Diabetic cardiomyopathy may be prevented or forestalled by good glycemic control, better control of hypertension and the use of cholesterol-lowering agents to prevent atherosclerosis. In addition, prevention or treatment of obesity and promotion of physical activity are advocated as important measures for preventing cardiovascular disease and diabetes.

Insulin Resistance and the Metabolic Syndrome

According to the report, studies suggest that insulin resistance is a multisystem disorder that induces multiple metabolic alterations. Metabolic risk factors that commonly occur in patients with insulin resistance are atherogenic dyslipidemia, hypertension, glucose intolerance and a prothrombotic state. The dyslipidemia is characterized by an elevated very-low-density lipoprotein level, small low-density lipoprotein (LDL) particles and a low high-density lipoprotein (HDL) level. Coagulation alterations that predispose the patient to arterial thrombosis include an increased fibrinogen level, increased plasminogen activator inhibitor-1 and various platelet abnormalities.

Risk Assessment and Clinical Evaluation

The report states that the first step in reducing the risk of cardiovascular disease in patients with diabetes is identification of risk factors such as cigarette smoking, hypertension, abnormal serum lipid levels, excess body weight and abdominal obesity, physical inactivity and a family history of cardiovascular disease.

Early detection of cardiovascular disease may reduce morbidity and mortality in patients with diabetes. Detection of subclinical disease requires a careful assessment for evidence of claudication, angina, dyspnea on exertion and cerebrovascular disease. Carotid and femoral arteries should be assessed for bruits and peripheral pulses should be evaluated. The ratio of ankle-to-brachial artery systolic blood pressure may serve as a marker for peripheral vascular disease. The urine should be checked for microalbuminuria. Electrocardiographic evidence of left ventricular hypertrophy is a strong predictor of morbidity and mortality from coronary heart disease.

Special considerations for exercise stress testing include the blunted blood pressure and heart rate responses that are often present in patients with diabetes. In addition, painless ST-segment depression is common in these patients, and the diagnostic specificity of ST-segment depression is often reduced in patients with diabetes because of a previous silent myocardial infarction, conduction abnormalities and increased left ventricular mass. An alternative to exercise testing is perfusion scintigraphy. Although not recommended routinely, ambulatory electrocardiographic monitoring may be useful for detecting silent ischemia.

The report notes that autonomic dysfunction is associated with a 50 percent mortality rate at five years. Periodic evaluation should include an assessment for evidence of autonomic dysfunction. Autonomic dysfunction increases the risk of general anesthesia and complications following elective surgery. Autonomic dysfunction may be present if two or more of the following abnormalities are found on examination: a resting heart rate (supine) of 100 beats per minute, an excessive diastolic blood pressure response to hand-grip exercise, an abnormal expiratory/inspiratory RR-interval ratio and postural hypotension.

Table 1 outlines important points for evaluating and monitoring the patient's renal status. Aggressive management of hypertension, to blood pressure levels of less than 130/85 mm Hg, is recommended as a measure to prevent the development of end-stage renal disease.

TABLE 1.

Important Considerations for Evaluation of Renal Status in Patients with Diabetes

Urine albumin and protein

Yearly screening for microalbuminuria seven years after the onset of type 1 diabetes (formerly called insulin-dependent diabetes) and type 2 diabetes (formerly called non–insulin-dependent diabetes) and in all hypertensive patients with diabetes; thereafter, test urine for albumin yearly.

Microalbuminuria: urine albumin of 30 to 300 mg per day or 30 to 300 mg per g of creatinine in the first morning urine specimen.*

Rule out other kidney diseases that cause proteinuria.

Detect increased urine albumin and protein.

Macroalbuminuria: urine protein > 300 mg per day (or > 300 mg per g of creatinine) in the first morning urine specimen.*

Nephrotic syndrome: urine protein > 3 g per day.

If either is present, further renal evaluation is necessary.

Patients with microalbuminuria or proteinuria and those with high serum creatinine or nephrotic syndrome should be evaluated by a nephrologist to detect other causes of kidney disease and to develop a treatment strategy.

Urinalysis

The presence of hematuria, pyuria and a large number of casts (e.g., red blood cell casts, white blood cell casts or > 2 granular casts per high-power field) is often an indication that a nondiabetic disease is also affecting the kidney. Such patients should be evaluated by a nephrologist to develop a treatment strategy if needed.

Blood pressure evaluation

If hypertension is present, exclude secondary causes, including advancing renal insufficiency.

Treatment with an ACE inhibitor may be preferred unless there is hyperkalemia or other complications.

BUN, serum creatinine and GFR

BUN is affected by the degree of renal insufficiency and dietary protein; therefore, it is not a satisfactory estimate of renal function.

The serum creatinine becomes high only after > 50% of kidney function is lost; therefore, it is not useful for detecting early renal insufficiency. A rising serum creatinine indicates progressive renal failure, and a plot of the reciprocal of serum creatinine versus time is useful for tracking the progressive decline in renal function.

The GFR is the most accurate estimate of the degree of renal dysfunction, but it generally requires administration of a radioisotope and at least four hours of the patient's time. The loss of GFR also provides the most accurate estimate of the rate of loss of kidney function.


ACE = angiotensin converting enzyme; BUN = blood urea nitrogen; GFR = glomerular filtration rate.

*—Urine collections must be done when there is no complicating condition that can elevate protein excretion; this includes fever, heavy exercise, poor glucose control, heart failure and urinary tract infection. Also, certain drugs can depress albumin excretion; these include nonsteroidal anti-inflammatory drugs and ACE inhibitors.

Adapted with permission from Grundy SM, Benjamin IJ, Burke GL, Chait A, Eckel RH, Howard BV, et al. Diabetes and cardiovascular disease: a statement for healthcare professionals from the American Heart Association. Circulation 1999;100:1134–46.

TABLE 1.   Important Considerations for Evaluation of Renal Status in Patients with Diabetes

View Table

TABLE 1.

Important Considerations for Evaluation of Renal Status in Patients with Diabetes

Urine albumin and protein

Yearly screening for microalbuminuria seven years after the onset of type 1 diabetes (formerly called insulin-dependent diabetes) and type 2 diabetes (formerly called non–insulin-dependent diabetes) and in all hypertensive patients with diabetes; thereafter, test urine for albumin yearly.

Microalbuminuria: urine albumin of 30 to 300 mg per day or 30 to 300 mg per g of creatinine in the first morning urine specimen.*

Rule out other kidney diseases that cause proteinuria.

Detect increased urine albumin and protein.

Macroalbuminuria: urine protein > 300 mg per day (or > 300 mg per g of creatinine) in the first morning urine specimen.*

Nephrotic syndrome: urine protein > 3 g per day.

If either is present, further renal evaluation is necessary.

Patients with microalbuminuria or proteinuria and those with high serum creatinine or nephrotic syndrome should be evaluated by a nephrologist to detect other causes of kidney disease and to develop a treatment strategy.

Urinalysis

The presence of hematuria, pyuria and a large number of casts (e.g., red blood cell casts, white blood cell casts or > 2 granular casts per high-power field) is often an indication that a nondiabetic disease is also affecting the kidney. Such patients should be evaluated by a nephrologist to develop a treatment strategy if needed.

Blood pressure evaluation

If hypertension is present, exclude secondary causes, including advancing renal insufficiency.

Treatment with an ACE inhibitor may be preferred unless there is hyperkalemia or other complications.

BUN, serum creatinine and GFR

BUN is affected by the degree of renal insufficiency and dietary protein; therefore, it is not a satisfactory estimate of renal function.

The serum creatinine becomes high only after > 50% of kidney function is lost; therefore, it is not useful for detecting early renal insufficiency. A rising serum creatinine indicates progressive renal failure, and a plot of the reciprocal of serum creatinine versus time is useful for tracking the progressive decline in renal function.

The GFR is the most accurate estimate of the degree of renal dysfunction, but it generally requires administration of a radioisotope and at least four hours of the patient's time. The loss of GFR also provides the most accurate estimate of the rate of loss of kidney function.


ACE = angiotensin converting enzyme; BUN = blood urea nitrogen; GFR = glomerular filtration rate.

*—Urine collections must be done when there is no complicating condition that can elevate protein excretion; this includes fever, heavy exercise, poor glucose control, heart failure and urinary tract infection. Also, certain drugs can depress albumin excretion; these include nonsteroidal anti-inflammatory drugs and ACE inhibitors.

Adapted with permission from Grundy SM, Benjamin IJ, Burke GL, Chait A, Eckel RH, Howard BV, et al. Diabetes and cardiovascular disease: a statement for healthcare professionals from the American Heart Association. Circulation 1999;100:1134–46.

Primary Prevention

The AHA statement notes that type 2 diabetes can be viewed as the end product of years of metabolic stress accompanying insulin resistance. As the report states, “the clock starts ticking for acceleration of atherogenesis long before the onset of hyperglycemia.” Early detection of risk factors associated with the metabolic syndrome is needed to institute primary prevention measures in patients at risk of diabetes. Evidence of insulin resistance includes the presence of abdominal obesity or borderline abdominal obesity, high-normal blood pressure or mild hypertension, high-normal triglycerides (150 to 250 mg per dL [1.70 to 2.82 mmol per L]), reduced HDL cholesterol (less than 40 mg per dL [1.05 mmol per L] in men and less than 50 mg per dL [1.30 mmol per L] in women) and borderline high-risk LDL cholesterol (130 to 159 mg per dL [3.35 to 4.10 mmol per L]). In some patients, impaired fasting glucose (110 to 126 mg per dL [6.10 to 7.00 mmol per L]) may be present. Impaired fasting glucose usually signifies longstanding insulin resistance and is a strong risk factor for type 2 diabetes. The report states that early implementation of primary measures for prevention of cardiovascular disease will probably delay the onset of type 2 diabetes as well as reduce the risk of cardiovascular disease.

Interventions for Risk Reduction in Cardiovascular Disease

According to the AHA statement, clinical trials show that comprehensive medical intervention in patients with diabetes and atherosclerotic cardiovascular disease can have a considerable impact. It can extend the overall rate of survival, improve quality of life, decrease the need for intervention procedures such as angioplasty and coronary artery bypass surgery, and reduce the incidence of subsequent myocardial infarction. Table 2 on page 567 summarizes the recommendations for interventions to reduce the risk in patients with diabetes and evidence of cardiovascular disease.

TABLE 2.

Guide to Risk Reduction in Patients with Diabetes and Cardiovascular Disease

Risk intervention Recommendation

Smoking cessation

Strongly encourage patient and family to stop smoking.

Provide counseling, nicotine replacement and formal cessation programs as appropriate.

Blood pressure control, with goal of ≤ 135/85 mm Hg

Initiate lifestyle modification (e.g., weight control, physical activity and moderate sodium restriction) in all patients with blood pressure of >135 mm Hg systolic or > 85 mm Hg diastolic.

Add antihypertensive agent, individualized to other patient requirements and characteristics (i.e., age, race, need for drugs with specific benefits) if blood pressure is not < 140 mm Hg systolic or < 90 mm Hg diastolic in three months or if initial blood pressure is > 160 mm Hg systolic or > 100 mm Hg diastolic.

Lipid levels, with primary goal of LDL ≤ 100 mg per dL (2.60 mmol per L) and secondary goal of HDL > 35 mg per dL (0.90 mmol per L) and TG < 200 mg per dL (2.26 mmol per L)

Start low-fat diet in all patients: ≤30 percent fat, < 7 percent saturated fat and < 200 mg per day of cholesterol.

Assess fasting lipid profile.

Immediately start cholesterol-lowering drugs if baseline LDL level is > 130 mg per dL (3.35 mmol per L). For LDL level < 100 mg per dL (2.60 mmol per L), no drug therapy is recommended; for LDL level of 100 to 129 mg per dL (2.60 to 3.35 mmol per L), consider adding drug therapy to diet; for LDL level of≥130 mg per dL (3.35 mmol per L), add drug therapy to diet. Suggested drug therapy: if TG level is < 200 mg per dL (2.26 mmol per L), use statin or resin; if TG level is 200 to 400 mg per dL (2.26 to 4.50 mmol per L), use statin or fibrate; if TG level is > 400 mg per dL (4.50 mmol per L), consider combined drug therapy (statin plus fibrate).

If HDL level is < 35 mg per dL (0.90 mmol per L), emphasize weight management and physical activity. Advise smoking cessation.

Glucose control, with goal of near-normal fasting glucose and hemoglobin A1c of ≤ 1 percent above normal

First-step therapy: weight reduction and exercise

Second-step therapy: oral hypoglycemic agents (sulfonylureas and/or metformin; ancillary: acarbose, glitazone)

Third-step therapy: insulin therapy

Physical activity, with a minimum of 30 minutes of exercise three to four times per week

Assess risk, preferably with exercise test, to guide prescription.

Encourage minimum of 30 to 60 minutes of moderate-intensity activity (walking, jogging, cycling or other aerobic activity) three to four times per week, supplemented by increase in daily lifestyle activities (e.g., walking breaks at work, using stairs, gardening, household work).

Maximum benefit: five to six hours per week

Advise medically supervised programs for moderate-risk and high-risk patients.

Weight management

Start intensive dietary therapy and appropriate physical activity in patients whose BMI is ≥25 kg per m2.

Particularly emphasize need for weight loss in patients with hypertension, elevated TG or elevated glucose levels.

Antiplatelet agents, anticoagulants

Start aspirin, 80 to 325 mg per day if it is not contraindicated.

Manage warfarin to INR of 2.0 to 3.5 in post-MI patients unable to take aspirin.

ACE inhibitors in post-MI patients

Start early after infarction in high-risk patients (anterior MI, previous MI, Killip class II [S3 gallop, rales, radiographic congestive heart failure]).

Continue indefinitely in all patients with left ventricular dysfunction (ejection fraction 40 percent) or symptoms of failure.

Use as needed to manage blood pressure or symptoms in other patients.

Beta blockers

Start in high-risk post-MI patients (arrhythmia, left ventricular dysfunction, inducible ischemia) at five to 28 days. Continue six months minimum. Observe usual contraindications. Appropriate use of beta blockers not contraindicated in patients with diabetes.

Use as needed to manage angina, rhythm or blood pressure in all other patients.

Estrogen

Observational studies (but not clinical trials) suggest benefit. Limited data in women with diabetes.

Individualize recommendation consistent with other health risks.


LDL = low-density lipoprotein; HDL = high-density lipoprotein; TG = triglycerides; BMI = body mass index; INR = international normalized ratio; MI = myocardial infarction; ACE = angiotensin converting enzyme.

Adapted with permission from Grundy SM, Benjamin IJ, Burke GL, Chait A, Eckel RH, Howard BV, et al. Diabetes and cardiovascular disease: a statement for healthcare professionals from the American Heart Association. Circulation 1999;100:1134–46.

TABLE 2.   Guide to Risk Reduction in Patients with Diabetes and Cardiovascular Disease

View Table

TABLE 2.

Guide to Risk Reduction in Patients with Diabetes and Cardiovascular Disease

Risk intervention Recommendation

Smoking cessation

Strongly encourage patient and family to stop smoking.

Provide counseling, nicotine replacement and formal cessation programs as appropriate.

Blood pressure control, with goal of ≤ 135/85 mm Hg

Initiate lifestyle modification (e.g., weight control, physical activity and moderate sodium restriction) in all patients with blood pressure of >135 mm Hg systolic or > 85 mm Hg diastolic.

Add antihypertensive agent, individualized to other patient requirements and characteristics (i.e., age, race, need for drugs with specific benefits) if blood pressure is not < 140 mm Hg systolic or < 90 mm Hg diastolic in three months or if initial blood pressure is > 160 mm Hg systolic or > 100 mm Hg diastolic.

Lipid levels, with primary goal of LDL ≤ 100 mg per dL (2.60 mmol per L) and secondary goal of HDL > 35 mg per dL (0.90 mmol per L) and TG < 200 mg per dL (2.26 mmol per L)

Start low-fat diet in all patients: ≤30 percent fat, < 7 percent saturated fat and < 200 mg per day of cholesterol.

Assess fasting lipid profile.

Immediately start cholesterol-lowering drugs if baseline LDL level is > 130 mg per dL (3.35 mmol per L). For LDL level < 100 mg per dL (2.60 mmol per L), no drug therapy is recommended; for LDL level of 100 to 129 mg per dL (2.60 to 3.35 mmol per L), consider adding drug therapy to diet; for LDL level of≥130 mg per dL (3.35 mmol per L), add drug therapy to diet. Suggested drug therapy: if TG level is < 200 mg per dL (2.26 mmol per L), use statin or resin; if TG level is 200 to 400 mg per dL (2.26 to 4.50 mmol per L), use statin or fibrate; if TG level is > 400 mg per dL (4.50 mmol per L), consider combined drug therapy (statin plus fibrate).

If HDL level is < 35 mg per dL (0.90 mmol per L), emphasize weight management and physical activity. Advise smoking cessation.

Glucose control, with goal of near-normal fasting glucose and hemoglobin A1c of ≤ 1 percent above normal

First-step therapy: weight reduction and exercise

Second-step therapy: oral hypoglycemic agents (sulfonylureas and/or metformin; ancillary: acarbose, glitazone)

Third-step therapy: insulin therapy

Physical activity, with a minimum of 30 minutes of exercise three to four times per week

Assess risk, preferably with exercise test, to guide prescription.

Encourage minimum of 30 to 60 minutes of moderate-intensity activity (walking, jogging, cycling or other aerobic activity) three to four times per week, supplemented by increase in daily lifestyle activities (e.g., walking breaks at work, using stairs, gardening, household work).

Maximum benefit: five to six hours per week

Advise medically supervised programs for moderate-risk and high-risk patients.

Weight management

Start intensive dietary therapy and appropriate physical activity in patients whose BMI is ≥25 kg per m2.

Particularly emphasize need for weight loss in patients with hypertension, elevated TG or elevated glucose levels.

Antiplatelet agents, anticoagulants

Start aspirin, 80 to 325 mg per day if it is not contraindicated.

Manage warfarin to INR of 2.0 to 3.5 in post-MI patients unable to take aspirin.

ACE inhibitors in post-MI patients

Start early after infarction in high-risk patients (anterior MI, previous MI, Killip class II [S3 gallop, rales, radiographic congestive heart failure]).

Continue indefinitely in all patients with left ventricular dysfunction (ejection fraction 40 percent) or symptoms of failure.

Use as needed to manage blood pressure or symptoms in other patients.

Beta blockers

Start in high-risk post-MI patients (arrhythmia, left ventricular dysfunction, inducible ischemia) at five to 28 days. Continue six months minimum. Observe usual contraindications. Appropriate use of beta blockers not contraindicated in patients with diabetes.

Use as needed to manage angina, rhythm or blood pressure in all other patients.

Estrogen

Observational studies (but not clinical trials) suggest benefit. Limited data in women with diabetes.

Individualize recommendation consistent with other health risks.


LDL = low-density lipoprotein; HDL = high-density lipoprotein; TG = triglycerides; BMI = body mass index; INR = international normalized ratio; MI = myocardial infarction; ACE = angiotensin converting enzyme.

Adapted with permission from Grundy SM, Benjamin IJ, Burke GL, Chait A, Eckel RH, Howard BV, et al. Diabetes and cardiovascular disease: a statement for healthcare professionals from the American Heart Association. Circulation 1999;100:1134–46.



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