Diabetes mellitus (DM) is historically characterized by hyperglycemia. The pathophysiologic processes causing hyperglycemia include insulin deficiency, impaired glucose disposal (insulin resistance), and increased hepatic glucose production. Type 1 diabetes mellitus (T1DM) results from an insulin deficiency state usually caused by immunologic damage to beta cells. Some patients with T1DM also have features of insulin resistance. Type 2 diabetes mellitus (T2DM) results from insulin resistance, often associated with central obesity, increased hepatic glucose production, and a progressive decline in beta cell function that is not immunologically mediated. Secondary forms of diabetes can occur as a result of pancreatectomy (insulin-deficient state), administration of glucocorticoids (glucocorticoid use may simply be unmasking a predisposition for diabetes), hemochromatosis, and rare syndromes such as antibodies to the insulin receptor. Gestational diabetes occurs during pregnancy as a result of production of glucose counterregulatory hormones; it and may be more common in patients genetically predisposed to develop T2DM.

This disease management article is limited to the common forms of diabetes, T1DM and T2DM. Approximately 20 million people in the United States have DM and one third are not aware of their diagnosis.

The processes by which hyperglycemia contributes to the complications of diabetes are not yet established. However, the following are considerations. Hyperglycemia is associated with the glycation of many proteins, including structural proteins. This can result in advanced glycation end products (AGEs), modified protein products that have been associated with many of the complications of diabetes. Glycation of low-density lipoprotein (LDL) makes it more susceptible to oxidation. Lipid oxidation is one of the proposed mechanisms for atherosclerosis. Hyperglycemia increases sorbitol accumulation in tissues and has been invoked as a mechanism for neuropathy and retinopathy. Hyperglycemia increases the concentration of protein kinase C β (PKC β) in the retina, which in turn is associated with increased concentrations of vascular endothelial cell growth factor (VEGF). VEGF contributes to the increased risk for proliferative changes in the eye and to loss of endothelial cell integrity and associated risk for macular edema.

Diagnostic criteria

The diagnosis of diabetes is based on several findings. The following criteria have been established by the American Diabetes Association (ADA) ¹ :

• Fasting glucose level higher than 126 mg/dL on two occasions. This fasting glucose value is consistently associated with the risk for retinopathy. This cut point value will miss a number of patients who have diabetes based on oral glucose tolerance testing results. Observational data suggest that this threshold fasting glucose for diagnosing diabetes may be too high, because patients with impaired glucose tolerance develop retinopathy.
• Random or casual glucose higher than 200 mg/dL, with symptoms of DM. This is a common way to diagnose DM. Many patients do not have obvious symptoms, but that should not alter the fact that a random blood glucose level in this range generally establishes the diagnosis of DM. This criterion is not affected by the time of the last meal.
• Oral glucose tolerance test (OGTT) result after a 75-g oral glucose load, 2-hour value higher than 200 mg/dL. The oral glucose tolerance test is not generally recommended in clinical practice. Such testing requires 3 days of high carbohydrate intake, and tests are not always reproducible.

Hemoglobin A_1c (HbA_1c) values are too insensitive to be used as a screening test for DM. Elevated values (e.g., higher than 6.2%) are usually associated with a diagnosis of DM, but patients can have DM with values below this range. Thus, elevated HbA_1c values are a specific test for the diagnosis of DM, but they are not highly sensitive.

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Lifestyle treatment

Medical Nutrition Treatment

Guidelines for medical nutrition therapy ^2-7 have been established by the ADA and are summarized in Box 1. The primary focus of these guidelines is targeted to outcomes including glycemic control, weight reduction (as appropriate), blood pressure control, and a favorable lipid profile. There is clear evidence that excess saturated fat in the diet has a detrimental effect on lipid profiles, and therefore restriction of saturated fat is recommended. The data supporting absolute restriction of carbohydrates are not robust, so the ADA guidelines allow flexibility in intake of carbohydrates and nonsaturated fat. Separate guidelines have been published about the carbohydrate content and composition of the diet. ⁸

The most important variable in prandial glycemic excursion is total carbohydrate intake. Low glycemic index foods consumed alone result in lower prandial glucose excursion than high glycemic index foods. However, in the context of a mixed meal, differences between low and high glycemic index foods are attenuated. The amount ^8-10 and source ^{10 , 11} of carbohydrates are important determinants of postprandial glucose. The relative effects of each have been recently studied. Brand-Miller and colleagues ^{12 , 13} have reported that they analyzed the relative impact of the glycemic index and total carbohydrate content of individual foods on glycemic load—the product of glycemic index and total grams of carbohydrate—using linear regression analysis. Carbohydrate content (total grams) alone explained 68% of the variation in glycemic load, and the glycemic index of the food explained 49%. When total carbohydrate and glycemic index were both included in the regression analysis, the glycemic index accounted for 32% of the variation.

Restriction of alcohol and sodium is generally advised. Supplements are not necessary in patients who are otherwise consuming a well-balanced diet. Many recommendations for weight management propose restriction of calories based on the degree of obesity and propose 30 to 45 minutes of exercise 3 to 5 days a week. Exercise is an important component of any regimen for weight reduction and glycemic control. Other nutritional guidelines for patients with diabetes are generally consistent with the ADA guidelines. ^5,14-28

Exercise

Guidelines for exercise have not always been specific with regard to exact exercise prescriptions, especially regarding aerobic and resistance exercises. ^14,29,30 The commonly proposed recommendation that 150 minutes of moderate-intensity (or 90 minutes of vigorous) aerobic exercise a week is generally the amount of exercise required to achieve benefits on glycemic control and reduce coronary heart disease (CHD) risk and has been supported by ADA/American Heart Association (AHA) recommendations. ^{6 , 7}

Regular exercise is encouraged, but complications of diabetes need to be taken into account. Injury to patients with loss of sensation in their feet is a limitation for weight-bearing exercise. Because of risk of CHD in patients with diabetes, appropriate screening for CHD should be performed before patients engage in any rigorous exercise program. ^14,17,29-32 Benefits of exercise include weight control and improved glycemic control, often due to improvement in insulin resistance.

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Complications

The complications of diabetes include retinopathy, nephropathy, neuropathy, and increased risk for atherosclerotic vascular disease. Diabetes is the leading cause of blindness in young people and is comparable with macular degeneration as a cause of blindness in older adults. DM is the leading cause of end-stage renal disease requiring dialysis or transplantation. DM is the leading cause of nontraumatic amputations of the lower extremity, a result of peripheral neuropathy and peripheral vascular disease. DM is associated with a twofold to fivefold increased risk for CHD. ³³

Two large trials—the Diabetes Control and Complications Trial (DCCT) and the United Kingdom Prospective Diabetes Study (UKPDS)—have demonstrated clear relation between glucose control and the risks for retinopathy (onset and progression), nephropathy (measured by albuminuria), and neuropathy (clinical and electromyographic measures). ^34-38 The relation between the degree of hyperglycemia and CHD risk has also been established. ^{39 , 40} Risk begins well below the glycemic threshold for the diagnosis of diabetes. ^{23,25-28,41,42}

Screening

Patients should be screened for diabetic complications (Table 1).

Diabetic Retinopathy

Dilated eye examinations by ophthalmologists or optometrists should be performed within 5 years of onset in T1DM and at the time of diagnosis in T2DM, because the actual date of onset is unknown in T2DM. ^{14 , 29} Follow-up examinations should be performed annually in patients with no or minimal background retinopathy. More frequent follow-up examinations should be performed in patients who have more advanced retinopathy. Handheld ophthalmoscopy in the office may be able to detect diabetic retinopathy but offers limited view of the retina and difficulty detecting diabetic macular edema. Macular edema is a significant cause of vision loss in DM. Macular edema is easier to detect with binocular vision and, in difficult cases, IV fluorescein angiography and confocal microscopy are used. Technology is available for screening with fundus photographs obtained in the physician's office and then read by an experienced reader. However, these methods are not yet sufficiently standardized to use as routine screening tools.

Diabetic Nephropathy

The hallmark of early diabetic nephropathy is albumin excretion. Sensitive assays to detect very low levels of albumin, or microalbuminuria, have been available for many years. ^{14 , 29} The simplest screening measure is a spot urine test adjusted for the urine creatinine level. Timed overnight collections and 24-hour collections may also be used. In general, microalbuminuria is defined as more than 30 mg albumin per gram of creatinine (spot urine test) or 30 to 299 mg per 24 hours and more than 300 mg/g creatinine (or 24 hours) as albuminuria. Serum creatinine determinations should be performed at least annually in patients with albuminuria; when estimated glomerular filtration rate (GFR) values are declining, more-specific measures of GFR (most commonly, creatinine clearance) should be used.

Peripheral Neuropathy

Monofilament testing in the office is the easiest way to test for the insensate foot. ^43-50 The 5.07-mm monofilament should be applied to the bottoms of the feet (Fig. 1). ⁵⁰ Any loss of sensation is associated with an increased risk for ulcer formation. Any patient who has had a foot ulcer is at increased risk for further foot ulcers.

Figure 1: Click to Enlarge

Patients should be instructed to look at their feet daily. Patients who have difficulty looking at their feet should have someone else look at their feet, especially if the patient has impaired vision, or should use a mirror, such as a magnifying shaving mirror, if they have trouble seeing the bottoms of their feet (see elsewhere in this section, “Prevention and Treatment of Leg and Foot Ulcers in Diabetes Mellitus”).

Coronary Heart Disease

Careful questioning about symptoms of ischemic coronary disease is still one of the most important ways to screen for symptomatic disease. Many patients with diabetes do not have typical exertional chest pain. Consequently, clinicians must ask about reduced exercise tolerance, dyspnea, or exercise-induced nausea.

Various studies have considered the issue of screening for CHD. ^{14,17,29,51-54} The guidelines and individual recommendations are not entirely concordant. Whereas nearly every group suggests stress tests for patients with symptoms of CHD or electrocardiographic changes suggesting ischemia, recommendations on screening for asymptomatic disease are less consistent. The ADA considers that candidates for a screening cardiac stress test should include those with a history of peripheral or carotid occlusive disease; persons with a sedentary lifestyle, who are older than 55 years, and who plan to begin a vigorous exercise program; and two or more of the risk factors noted earlier. ²⁹ The American Association of Clinical Endocrinologists (AACE) guidelines state:

Screening for asymptomatic coronary artery disease is an important consideration in patients with diabetes. An appropriate protocol for such screening has not been adequately tested. Increasing age, gender, cardiovascular risk factors,microalbuminuria, and retinopathy may identify high-risk groups for whom such testing is indicated¹⁴

The AHA consensus group has provided a thoughtful approach to screening for CHD in patients with diabetes. They noted:

Screening is defined here as the detection of disease in asymptomatic persons. Because screening tests are intended for widespread application, they 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.¹⁷

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; that is, its usefulness or efficacy is less well established by evidence or opinion. ⁵⁴ They add that exercise testing “might be useful in people with heightened pretest risk.” Most consensus statements and guidelines on diabetes and CHD have suggested that noninvasive cardiac testing be performed in patients with diabetes and one additional criterion: peripheral arterial disease, cerebrovascular disease, rest changes on the electrocardiogram (ECG), or the presence of two or more major coronary vascular disease (CVD) risk factors. According to these guidelines, risk assessment begins with a medical history, including special attention to symptoms of atherosclerotic disease, such as angina, claudication, or erectile dysfunction. Electrocardiographic changes showing left ventricular hypertrophy and ST-T changes suggest increased cardiovascular risk. The ongoing DIAD study, which is designed to determine risk factors associated with clinically silent myocardial disease using stress tests with cardiac imaging, has suggested that the presence of neuropathy may be one of the most important predictors of cardiovascular risk.

It is not yet clear exactly how noninvasive testing changes risk management strategies in diabetes, because DM is already considered a coronary heart disease risk equivalent. Thus, noninvasive testing should be targeted as much as possible to detect patients who might have CHD amenable to surgical intervention. Whereas noninvasive screening in asymptomatic patients might detect disease amenable to percutaneous intervention or coronary artery bypass grafting, the cost-effectiveness and determination of how much such screening affects long-term outcomes are still uncertain.

I believe that careful attention to history of changes in exercise tolerance, atypical symptoms that suggest angina, or suggestive electrocardiographic abnormalities are reasons to consider stress testing. In addition, dyslipidemia, obesity, and hypertension, albuminuria and a family history of CHD may be reasons to consider stress testing in patients who do not have clinical symptoms of CHD. This approach is most consistent with the AACE guidelines and should select patients at highest risk for CHD. In the absence of robust evidence, as noted by the AHA, physicians still need to make decisions about patients who might have silent myocardial disease. Soon, imaging techniques such as computed tomography (CT) angiography will help characterize patients at risk for an acute event, even in the absence of symptoms.

Management of Coronary Heart Disease Risk

Dyslipidemia

Guidelines for the management of dyslipidemia have been published by the National Cholesterol Education Program (NCEP; several expert panels since 1988), AACE, ACP, ADA, ACC, and AHA (Table 2). They are generally consistent in recommending aggressive lipid-lowering management in diabetes, which is considered a coronary risk equivalent.*

Physicians should note that not all patients with diabetes have a 20% risk of a cardiac event over a 10-year period as determined by the UKPDS risk engine, ³⁹ so some discretion may be used with the guidelines. The proposed LDL cholesterol level targets are as follows:

• The LDL cholesterol level is lower than 100 mg/dL for any patient with DM.
• If the LDL cholesterol level is below 100 mg/dL, but triglyceride (and very LDL [VLDL] cholesterol) levels are elevated, then the non–high-density lipoprotein (HDL) cholesterol level should be lower than 130 mg/dL.
• The optional guidelines for patients at very high risk, such as diabetic patients with a prior myocardial infarction (MI), are an LDL cholesterol level lower than 70 mg/dL (and non-HDL cholesterol level lower than 100 mg/dL).
• Patients who have an LDL cholesterol level lower than 100 mg/dL without medication should be treated to achieve a more than 30% reduction in their LDL cholesterol level.

These guidelines were developed based on findings from lipid-lowering trials that included diabetic patients and were confirmed by subsequent trials.

Post hoc analyses of diabetic patients who were included in lipid-lowering trials have supported the notion that diabetic patients have comparable relative reductions (or perhaps greater absolute reductions) in the risk for CHD events than their nondiabetic counterparts. These data have been summarized as part of the ACP guidelines. ²⁰ The ADA and AHA guidelines ^6,7,29,55,56 have suggested an LDL cholesterol level target of less than 100 mg/dL for patients with diabetes and an optional target of less than 70 mg/dL for patients with DM who already have CHD; this recommendation is based on several clinical trials including, the HPS, ASCOT-LLA, and CARDS trials. ^57-60 The CARDS trial, in 2838 patients with T2DM, showed a 37% reduction in cardiovascular events, with a mean in-trial LDL cholesterol level of approximately 80 mg/dL in the atorvastatin group compared with 119 mg/dL in the placebo group. The HPS and CARDS studies have shown favorable effects in diabetic patients whose LDL cholesterol levels were lower than 100 mg/dL. In addition, these guidelines have recommended that in patients with elevated triglyceride levels, and a corresponding increase in VLDL cholesterol levels, that the non-HDL cholesterol value (LDL plus VLDL cholesterol level) be set at 30 mg/dL higher than the LDL target—that is, a non-HDL cholesterol level lower than 130 mg/dL, with an optional target of less than 100 mg/dL.

Since these guidelines were written, two major trials have been reported whose results are less convincing about the benefits of the lower LDL cholesterol level target and the effects of triglyceride level reduction. The ASPEN trial studied 2410 T2DM subjects who were randomized to 10 mg atorvastatin versus placebo. ⁶¹ At baseline, LDL cholesterol levels were 113 mg/dL (atorvastatin group) and 114 mg/dL (placebo group). The atorvastatin group had a mean in-treatment LDL cholesterol level of 79 mg/dL, and the placebo group's level was essentially unchanged (LDL cholesterol level, 113 mg/dL). This difference was associated with a 10% reduction in the primary composite end point (P was not statistically significant [NSS]) and a 27% reduction in fatal-nonfatal MI (P = NSS). Although these results were not as robust as in the similarly designed CARDS study, the authors concluded that the “present data do not detract from the imperative that the majority of diabetic patients, especially those with existing CHD, are at risk of CHD and deserve LDL cholesterol lowering to the currently recommended targets.” ⁶¹

The FIELD trial was designed to assess the effects of fenofibrate (vs. placebo) on cardiovascular disease events in 9795 T2DM subjects. ^{62 , 63} The difference in total cardiovascular events was 11% (P = .035) and in MI plus CHD death it was 11% (P = .16). This trial was confounded by very high levels of statin drop-in, especially in the placebo arm. The ACCORD trial results should help clarify the effects of fibrates. In the lipid-lowering arm of this trial, the participants were all provided simvastatin therapy and then randomized to fenofibrate versus placebo. Results should be available by 2010.

Hypertension and Renin-Angiotensin-Aldosterone System Blockade

Blood pressure control has a greater effect on reducing the risk for stroke than the risk for MI. The largest blood pressure trials in diabetic patients have demonstrated favorable effects on reduction in CVD. Current clinical guidelines recommend BP targets of 130/80 (or 130/85) mm Hg. ^{14,29,64,62,63} Few clinical trials have actually achieved these goals, but there does not appear to be any risk in reaching these targets. Multidrug regimens (often three or more drugs) are usually required. Based on several studies (especially HOPE and the EUROPA study, which demonstrated favorable cardiovascular effects with the ACE inhibitors ramipril and perindopril, respectively, in diabetic cohorts), these agents should be considered part of initial therapy in hypertensive T2DM subjects. ^65,66-68 ONTARGET (N = 25,620, 38% with diabetes) compared ramipril to telmisartan and to the combination of both drugs on CVD outcomes. There were no differences among the three arms. ⁶⁹ The beneficial effects could not be entirely attributed to blood pressure reduction in these trials.

Aspirin

Aspirin (ASA) therapy is recommended for patients with diabetes in the ADA and other guidelines. ^{29 , 70} There are few data to suggest benefits for patients without established CHD. Because most patients with T2DM are at increased risk for CHD compared with their nondiabetic counterparts, aspirin use in high-risk patients is prudent. The guidelines originally recommended 81 to 325 mg daily because there are no outcomes data comparing ASA doses. ADA/AHA guidelines now recommend 75 to 162 mg daily. ^{6 , 7} The concept of aspirin resistance is evolving, and some patients with diabetes may be aspirin resistant. If this observation is supported by future studies, then doses above 81 mg may be prudent for diabetic patients.

Smoking

All the DM- and CHD-related guidelines recommend smoking cessation.

Glycemic Control

Intervention trials have shown a somewhat modest relation between glycemic control and CHD risk. In the UKPDS trial, a delta HbA_1c value of 0.9% was associated with a 14% reduction in the risk for MI (P = .052) in the intention to treat analyses and a 16% reduction for every 1% HbA_1c level change as a post hoc observational analysis. ^36,38,71 The metformin arm in obese patients in the UKPDS demonstrated a 39% reduction in MI compared with the conventional arm (P = .010). ³⁷ ACCORD (N = 10,251) and ADVANCE (N = 11,140) did not demonstrate beneficial effects of intensive control (HbA_1c < 7.0%) on CVD events. ^{72 , 73}

In the DCCT/EDIC study, there was no statistically significant reduction in CHD risk at the end of the DCCT—this was expected, because the trial included a population at low risk for CHD at randomization—but a 42% reduction (P = .016) in risk of any cardiac event during the duration of the DCCT/EDIC study, 20 years in subjects randomized early in the trial. ⁷⁴ Thus, the annualized effect of glycemic control on CHD risk is less than that generally associated with other interventions, especially lipid lowering.

Summary

The watchword of the ADA several years ago was “diabetes is serious.” Careful screening for complications, including retinopathy, nephropathy, and neuropathy clearly are associated with opportunities to reduce the risk for disease progression. Aggressive interventions with glycemic control, as well as management of lipids and blood pressure, seem to have favorable effects on many complications of diabetes. Aspirin therapy also reduces the risk for CHD risk in patients with DM. These screening and intervention strategies are supported by robust observational and intervention trial data and, in turn, are endorsed by the various organizations that have written disease management guidelines.

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Summary

• Diabetes mellitus is a leading cause of blindness, end-stage renal disease, and nontraumatic lower extremity amputations.
• Diabetes mellitus increases the risk for coronary heart disease by two- to fivefold.
• Glycemic control is associated with a reduced risk for the microvascular and neuropathic complications of diabetes mellitus.
• Treatment of CHD risk factors, especially dyslipidemia, is associated with a reduced risk for CHD.
• Early detection of microvascular and neuropathic complications and implementation of appropriate treatment strategies, such as laser therapy (retinopathy), use of ACE inhibitors and ARBs (nephropathy), and proper footwear (neuropathy), will reduce the risk for adverse outcomes from these complications.

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Suggested Readings

• Adler AI, Stratton IM, Neil HA, et al: Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): Prospective observational study. BMJ. 2000, 321: 412-419.
• American Diabetes Association. Standards of medical care in diabetes-2007. Diabetes Care. 2007, 30: (Suppl 1): S4-S41.
• Bantle JP, Wylie-Rosett J, Albright AL, et al: Nutrition recommendations and interventions for diabetes-2006: A position statement of the American Diabetes Association. Diabetes Care. 2006, 29: 2140-2157.
• Buse JB, Ginsberg HN, Bakris GL, et al: Primary prevention of cardiovascular diseases in people with diabetes mellitus: A scientific statement from the American Heart Association and the American Diabetes Association. Diabetes Care. 2007, 30: 162-172.
• Diabetes Control and Complications Trial Research Group. The relationship of glycemic exposure (HbA_1c) to the risk of development and progression of retinopathy in the Diabetes Control and Complications Trial. Diabetes. 1995, 44: 968-983.
• Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. Retinopathy and nephropathy in patients with type 1 diabetes four years after a trial of intensive therapy. N Engl J Med. 2000, 342: 381-389.
• Gibbons RJ, Balady GJ, Beasley JW, et al: ACC/AHA guidelines for exercise testing: Executive summary. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Exercise Testing). Circulation. 1997, 96: 345-354.
• Grundy SM, Cleeman JI, Merz CN, et al: Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Arterioscler Thromb Vasc Biol. 2004, 24: e149-e161.
• Stratton IM, Adler AI, Neil HA, et al: Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): Prospective observational study. BMJ. 2000, 321: 405-412.
• Strippoli GF, Craig M, Deeks JJ, et al: Effects of angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists on mortality and renal outcomes in diabetic nephropathy: Systematic review. BMJ. 2004, 329: 828.