Online Medical Reference

Diabetes Mellitus: Management of Microvascular and Macrovascular Complications

Robert. S. Zimmerman

Published: September 2016

The management of type 1 and 2 diabetes mellitus (DM) requires addressing multiple goals, with the primary goal being glycemic control. Maintaining glycemic control in patients with diabetes prevents many of the microvascular and macrovascular complications associated with diabetes. This chapter presents a review of the prevalence, screening, diagnosis, and management of these complications.


Microvascular complications of diabetes are those long-term complications that affect small blood vessels. These typically include retinopathy, nephropathy, and neuropathy.

  • Retinopathy is divided into two main categories: Nonproliferative retinopathy and proliferative retinopathy.
    • Nonproliferative retinopathy is the development of microaneurysms, venous loops, retinal hemorrhages, hard exudates, and soft exudates.
    • Proliferative retinopathy is the presence of new blood vessels, with or without vitreous hemorrhage. It is a progression of nonproliferative retinopathy.
  • Diabetic nephropathy is defined as persistent proteinuria. It can progress to overt nephropathy, which is characterized by progressive decline in renal function resulting in end-stage renal disease.
  • Neuropathy is a heterogeneous condition associated with nerve pathology. The condition is classified according to the nerves affected and includes focal, diffuse, sensory, motor, and autonomic neuropathy.

Macrovascular complications of diabetes are primarily diseases of the coronary arteries, peripheral arteries, and cerebrovasculature. Early macrovascular disease is associated with atherosclerotic plaque in the vasculature supplying blood to the heart, brain, limbs, and other organs. Late stages of macrovascular disease involve complete obstruction of these vessels, which can increase the risks of myocardial infarction (MI), stroke, claudication, and gangrene. Cardiovascular disease (CVD) is the major cause of morbidity and mortality in patients with diabetes.

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Retinopathy. In patients with type 1 DM, 13% have retinopathy at 5 years and 90% have retinopathy after 10 to 15 years; approximately 25% will develop proliferative retinopathy after 15 years.[1]

In patients with type 2 DM, 40% of patients taking insulin and 24% of patients taking oral hypoglycemic agents will develop retinopathy at 5 years. After 15 to 19 years, the percentages increase to 84% and 53%, respectively. Proliferative retinopathy develops in 2% of patients with type 2 DM for longer than 5 years and in 25% of patients with diabetes for 25 years or longer.[2]

Nephropathy. The prevalence of nephropathy in diabetes has not been determined. Approximately 30% of patients with type 1 DM─and 5% to 10% of those with type 2 DM─become uremic. [3] Diabetic nephropathy is a leading cause of end-stage renal disease.

Neuropathy. The prevalence of neuropathy in patients with diabetes is 7% at 1 year, increasing to 50% at 25 years for both type 1 and type 2 DM.[4]

Macrovascular. Macrovascular complications in patients with diabetes cause an estimated two- to four-fold increased risk of coronary artery disease (CAD), peripheral arterial disease, and cerebrovascular disease.[5] An estimated 37% to 42% of all ischemic strokes in Americans are attributable to the effects of diabetes, alone or in combination with hypertension.[6] The prevalence of CAD or stroke in patients with diabetes is approximately 34% in both men and women. The prevalence of peripheral vascular disease in patients with diabetes aged 30 years or older is 26%.[7]

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Retinopathy. Microaneurysm formation is the earliest manifestation of diabetic retinopathy. Microaneurysms may form due to the release of vasoproliferative factors, weakness in the capillary wall, or increased intra-luminal pressures. Microaneurysms can cause vascular permeability in the macula, which can lead to macular edema that threatens central vision. Obliteration of retinal capillaries can lead to intraretinal microvascular abnormalities. As capillary closure becomes extensive, intraretinal hemorrhages develop.

Proliferative retinopathy develops due to ischemia and release of vasoactive substances, such as vascular endothelial growth factor, which stimulate new blood vessel formation as a progression of nonproliferative retinopathy. These vessels may erupt through the surface of the retina and grow on the posterior surface of the vitreous humor. These vessels are very friable and can lead to vitreous hemorrhages. The vitreous humor can contract and lead to retinal detachment.

Nephropathy. Two pathophysiologic pathways for diabetic nephropathy have been identified. First, diabetic nephropathy can result from increased glomerular capillary flow that, in turn, results in increased extracellular matrix production and endothelial damage. This leads to increased glomerular permeability to macromolecules. Mesangial expansion and interstitial sclerosis can ensue, which have the potential to cause glomerular sclerosis. A second pathway termed nonalbuminuric renal impairment is due to macrovascular and/or repeated unresolved episodes of acute kidney injury. Reduced glomerular filtration rate (GFR) and albuminuria are risk factors for cardiovascular events whereas albuminuria predicted death and progression to end stage renal disease better than GFR loss.

Neuropathy. The pathophysiology of neuropathy is complex. Diabetes is associated with dyslipidemia, hyperglycemia, and low insulin and growth factor abnormalities. These abnormalities are associated with glycation of blood vessels and nerves. In addition, autoimmunity may affect nerve structure. Trauma and nerve entrapment can lead to structural nerve damage including segmental demyelination, axonal atrophy and loss, and progressive demyelination. These effects cause neuropathy.

Macrovascular. The macrovascular complications of diabetes result from hyperglycemia, excess free fatty acid, and insulin resistance. These cause increased oxidative stress, protein kinase activation, and activation of the receptor for advanced glycation end products, factors that act on the endothelium.

  • First, decreased nitric oxide, increased endothelin, and increased angiotensin II cause vasoconstriction that results in hypertension and vascular smooth muscle cell growth.
  • Second, decreased nitric oxide, activated nuclear factor-KB, increased angiotensin II, and activation of activated protein-1 increase inflammation, which results in the release of chemokines, cytokines, and expression of cellular adhesion molecules.
  • Third, decreased nitric oxide, increased tissue factor, increased plasminogen activator inhibitor-1, and decreased prostacyclin result in thrombosis, hypercoagulation, platelet activation, and decreased fibrinolysis.

These pathways ultimately lead to atherosclerosis, the cause of the macrovascular complications of diabetes.

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Signs and Symptoms

Retinopathy. Symptoms of retinopathy are minimal until advanced disease ensues with loss or blurring of vision. Signs of nonproliferative retinopathy include microaneurysms, venous loops, retinal hemorrhages, hard exudates, and soft exudates. Proliferative retinopathy can include new vessels in the eyes or vitreous hemorrhage.

Nephropathy. The earliest sign of nephropathy is hypertension, which often coincides with the development of microalbuminuria. As nephropathy worsens, patients can develop edema, arrhythmias associated with hyperglycemia, or symptoms related to renal failure.

Neuropathy. Signs and symptoms of neuropathy depend on the type of neuropathy that develops. Most commonly, patients develop symptomatic distal polyneuropathy. Signs include decreased or total loss of ankle jerk reflexes and vibratory sensation, with hyperalgesia and calf pain in some patients. These usually present in a "stocking and glove" distribution. Wasting of the small muscle of the hands and feet also can occur.

Patients may present with focal neuropathies due to either mononeuritis or entrapment syndromes. These produce focal neurologic deficits confined to a single nerve. A rare but severe form of diabetic neuropathy is diabetic amyotrophy, which begins with pain followed by severe weakness and spreads from unilateral to bilateral. It resolves spontaneously in 18 to 24 months.

Macrovascular. Patients with diabetes-associated CVD can present with stable or unstable angina pectoris, MI, or dysrhythmias; however, many patients have unrecognizable symptoms. Patients with cerebral vascular disease can present with a sudden onset of a focal neurologic deficit such as facial droop, hemiparesis, or isolated weakness of an arm or leg. Dizziness, slurred speech, gait difficulties, and visual loss also can be the presenting symptoms.

Peripheral vascular disease is recognized by exertional leg pain that can progress to pain at rest and ischemic ulcers. Most cases are asymptomatic.

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Patients with diabetes should be screened regularly, at least every 6 months, for retinopathy, nephropathy, and neurology complications (Table 1). Those with uncontrolled diabetes should be examined more frequently.

Table 1. Screening for micro- and macrovascular complications in patients with diabetes.
Complication Detection
  • Dilated eye examination (fundus photography)
  • Intravenous fluorescein angiography
  • Optical coherence imaging
Nephropathy Urine micoalbumin
Neuropathy Monofilament testing
Hypertension Measure blood pressure, every visit
Dyslipidemia Fasting lipid profiles, at least annually


Dilated eye examinations by an ophthalmologist or optometrist should be performed within 5 years of onset in type 1 DM and at the time of diagnosis in type 2 DM, because the actual date of onset is hard to determine in type 2 DM. Follow-up eye examinations should be performed annually in patients with no or minimal background retinopathy. More frequent follow-up examinations are needed in those who have more advanced retinopathy.

Handheld ophthalmoscopy may be able to detect diabetic retinopathy, but it offers limited view of the retina and has difficulty detecting diabetic macular edema, a significant cause of vision loss in diabetes. Retinopathy is easier to detect with binocular vision. In difficult cases, IV fluorescein angiography and confocal microscopy are used. Technology is available for screening with fundus photographs obtained in the practitioner's office and then read by an expert. However, these do not show a complete view of the retina and do not include other aspects of the eye examination, such as eye pressure, and, thus, cannot replace yearly eye evaluations.


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. The simplest screening measure is a spot urine test adjusted for the urine creatinine level. Timed overnight collections or 24-hour collections also may 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 gram of creatinine (or 24 hours) as albuminuria. Serum creatinine determinations should be performed at least annually in patients with albuminuria. When estimated glomerular filtration rate (eGFR) values are declining, more specific measures of GFR (most commonly, creatinine clearance) should be used.

Peripheral Neuropathy

Monofilament testing performed in the office is the easiest way to check for the insensate foot. The 5.07 mm monofilament is applied to the bottoms of the feet (Figure 1). Any loss of sensation is associated with an increased risk for ulcer formation. A patient who has had a foot ulcer is at increased risk for additional foot ulcers.

Patients should be instructed to examine their feet daily. Patients who have difficulty examining their feet should seek assistance, especially if they have impaired vision. The use of a mirror can help patients see the bottoms of their feet (see the chapter, "Prevention and Treatment of Leg and Foot Ulcers in Diabetes Mellitus").

Cardiovascular Disease

Careful questioning about symptoms of ischemic coronary disease is still one of the most important ways to screen for CVD. 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 CVD. The guidelines and individual recommendations are not entirely concordant. Whereas nearly every group suggests stress tests for patients with symptoms of CVD or electrocardiographic changes suggesting ischemia, recommendations on screening for asymptomatic disease are less consistent.

The American Diabetes Association (ADA) considers that candidates for cardiac stress testing should include those with a history of peripheral or carotid occlusive disease; those with a sedentary lifestyle who are older than 55 years and who plan to begin a vigorous exercise program; and those with two or more risk factors for CVD.[8]

The American Association of Clinical Endocrinologists (AACE) guidelines state the following:

Screening for asymptomatic coronary artery disease with various stress tests in patients with T2D has not been clearly demonstrated to improve cardiac outcomes and is therefore not recommended.[9]

The American Heart Association (AHA) consensus group created the following approach to screening for CAD in patients with diabetes:

Screening is defined 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 outcomes.[10]

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, meaning that its usefulness or efficacy is less well established by evidence or opinion.[11] They note that exercise testing might be useful in people with heightened pretest risk.

Most consensus statements and guidelines on diabetes and CAD 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 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 CVD risk. Data from the ongoing DIAD study (Detection of Ischemia in Asymptomatic Diabetics),[12] 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 CVD risk.

It is not yet clear how results from noninvasive testing can change risk management strategies in patients with diabetes, because diabetes is already considered a CVD risk equivalent. Thus, noninvasive testing should be targeted as much as possible to identify patients who might have CVD that is 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 effects on long-term outcomes are still uncertain.

Careful attention to a patient's history of changes in exercise tolerance, atypical symptoms that suggest angina, or suggestive ECG abnormalities are reasons to consider stress testing. In addition, dyslipidemia, obesity, hypertension, albuminuria, and a family history of CVD may be reasons to consider stress testing in patients who do not have clinical symptoms of CVD. This approach is most consistent with the AACE guidelines and should select patients at highest risk for CVD. In the absence of robust evidence, as noted by the AHA, practitioners need to make decisions about patients who might have silent myocardial disease.

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The diagnosis of retinopathy is based on the findings of eye exams to determine if the patient has clinically significant macular edema, proliferative retinopathy, or severe nonproliferative retinopathy. The progressive changes in the retina that occur in patients with diabetes include the following:

  1. Formation of retinal capillary microaneurysms;
  2. Development of abnormal vascular permeability;
  3. Ischemia;
  4. New vessel and fibrous tissue proliferation of the surface of the retina and optic disk;
  5. Contraction of the fibrovascular proliferations and the vitreous.[13]


The diagnosis of nephropathy is initially based on development of microalbuminuria. Microalbuminuria is defined as an albumin excretion rate 20 to 200 mcg/min. Because the average daily albumin excretion rate varies by up to 40% between those with diabetes and those without, it is recommended that three urine collections be taken over several weeks before making this diagnosis. Overt nephropathy is defined as an albumin excretion rate >300 mg/24 hours. This is associated with a linear decline in GFR ranging from 0.1 to 2.4 mL/min/month.

The following are the stages of chronic kidney disease:[14]

Stage 1: GFR >90 mg/24 hours.

Stage 2: GFR is mildly decreased at 60 to 89 mg/24 hours.

Stage 3: GFR is 30 to 59 mg/24 hours.

Stage 4: GFR is 15 to 29 mg/24 hours.

Stage 5: End-stage nephropathy with a GFR <15 mg/24 hours.


The diagnosis of neuropathy, defined by loss of ankle jerk reflexes, is based on finding focal (individual root) or diffuse (entire limb) involvement. Findings can be asymmetric (mononeuritis multiplex) or symmetric conforming to a distal-to-proximal gradient of involvement (most common). Electrodiagnostic studies can confirm peripheral nerve disease and define the pattern of disease. Autonomic neuropathy is diagnosed in patients with gastroparesis or orthostatic hypotension.

Cardiovascular Disease

The diagnosis of CVD can be confirmed by several diagnostic and imaging studies. A resting 12-lead ECG is not sensitive enough to identify disease in patients with stable angina. Cardiovascular stress testing can be assessed with ECG assessment during exercise, dobutamine, dipyridamole, or adenosine. Echocardiography can enhance the sensitivity of the test. Alternatively, nuclear stress testing with thallium 201 or technetium 99m in association with dipyridamole or adenosine can be used. Significant CAD is identified by relative hypoperfusion in peak stress images. Coronary arteriography can confirm CAD.

The diagnosis of a stroke is based on a patient developing symptoms of focal neurologic deficit and can be confirmed by a CT scan or MRI. CT angiography can be used to identify the location of vascular occlusion and assess for salvageable brain tissue.

The diagnosis of peripheral arterial disease is diagnosed by determining the ankle brachial index (ABI). This is the ratio of the Doppler-determined systolic ankle pressure over the systolic brachial pressure. An ABI less than 0.9 has a sensitivity of 95% and a specificity of 100% in detecting peripheral arterial disease. An ABI greater than 1.4 reflects calcified arteries. It is associated with increased risk of foot ulcers and CVD. If revascularization is being considered, other tests including duplex ultrasonography, MR angiography, and CT angiography can be used to determine specific sites of surgical intervention.

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Management: Lifestyle

Appropriate management of the microvascular and macrovascular complications of diabetes requires practitioners to treat a comprehensive range of factors that focus on several areas including nutritional intake, control of blood glucose, lifestyle and activity, blood pressure, and lipids.

Medical-Nutrition Therapy

Guidelines for medical-nutrition therapy have been established by the ADA and are summarized in Table 2.[15] The primary focus of these guidelines is to improve outcomes by improving glycemic control, reducing weight (as appropriate), and controlling blood pressure and lipids. There is clear evidence that excess saturated fat in the diet has a detrimental effect on lipid profiles; therefore, restriction of saturated fat is recommended. Data supporting absolute restriction of carbohydrates are not robust, so the ADA guidelines allow flexibility in intake of carbohydrates. The ADA has published separate guidelines for the carbohydrate content and composition of the diet.[16]

The most important variable in prandial glycemic excursion is total carbohydrate intake. Consumption of low glycemic index foods results in lower prandial glucose excursion than consuming high glycemic index foods. In the context of a mixed meal, however, differences between low and high glycemic index foods are attenuated.

The amount and source of carbohydrates are important determinants of postprandial glucose levels. In studies of 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 carbohydrates—carbohydrate content (total grams) explained 68% of the variation in glycemic load and the glycemic index of the food explained 49%.[17,18] When total carbohydrate content 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. Nutritional supplements are not necessary in patients who are consuming a well-balanced diet. Many recommendations for weight management propose calorie restriction based on the degree of obesity along with 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.

Table 2. Goals of medical-nutrition therapy for patients with diabetes.

Achieve optimal metabolic outcomes by attaining and maintaining the following:

  1. Blood glucose levels in the normal range or as close to normal as is safely possible
  2. Lipid and lipoprotein profiles that reduce risk for macrovascular disease
  3. Blood pressure levels that reduce risk for vascular disease
  4. Modify nutrient intake and lifestyle as appropriate to prevent and treat obesity, dyslipidemia, CVD, hypertension, and nephropathy

Improve health through healthy food choices and physical activity.

Address individual nutritional needs, taking into consideration personal and cultural preferences and lifestyle while respecting the individual's wishes and willingness.

Specific patient populations
Children and adolescents with type 1 DM
Provide adequate energy to ensure normal growth and development.
Integrate insulin regimens into usual eating and physical activity habits.
Children and adolescents with type 2 DM
Facilitate changes in eating and physical activity habits that reduce insulin resistance and improve metabolic status.
Pregnant and lactating women
Provide adequate energy and nutrients needed for optimal outcomes.
Older adults
Provide for the nutritional and psychosocial needs of aging adults.
Patients treated with insulin or insulin secretagogues
Provide self-management education for treatment (and prevention) of hypoglycemia, acute illnesses, and exercise-related blood glucose problems.
Population at risk for diabetes
Decrease risk by encouraging physical activity and promoting food choices that facilitate moderate weight loss or at least prevent weight gain.

Source: Bantle JP Diabetes Care 2006. [15]


Guidelines for exercise have not always been specific with regard to exact exercise prescriptions, especially regarding aerobic and resistance exercises. The commonly proposed recommendation is for 150 minutes of moderate-intensity (or 90 minutes of vigorous) aerobic exercise per week to achieve benefits on glycemic control and reduce CVD risk. It is supported by ADA/AHA recommendations.[19]

Regular exercise is encouraged, but complications of diabetes need to be taken into account. For example, patients with loss of sensation in their feet should limit weight-bearing exercise. Because of the CVD risk in patients with diabetes, appropriate screening for CVD should be performed before patients engage in an exercise program. Benefits of exercise include weight control and improved glycemic control, often due to reduced insulin resistance.


All diabetes and CVD-related guidelines recommend smoking cessation.

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Management: Microvascular Risks

Prevention is the optimal approach to managing the microvascular complications of diabetes. The two main approaches to preventing retinopathy and nephropathy are intensive glycemic control and aggressive control of hypertension. Intensive glycemic control has been the most effective approach to preventing neuropathic complications of diabetes.

The Wisconsin Epidemiologic Study demonstrated that in patients with diabetes, higher baseline hemoglobin A1c (HbA1c) levels correlated with increased incidence of retinopathy, progression of retinopathy, and progression of proliferative retinopathy.[1,2]

The Diabetes Control and Complications Trial [20] (DCCT) compared intensive insulin therapy (insulin pump or multiple daily injections) versus conventional therapy (one or two injections per day) in 1,441 patients with type 1 DM (615 with mild to moderate retinopathy). After a mean of 6.5 years, intensive therapy effectively slowed or delayed the onset of diabetic retinopathy, nephropathy, and neuropathy in insulin-dependent patients. In a 4-year follow-up after the study ended,[21] the reduced risks of progressive retinopathy (proliferative retinopathy, macular edema, and need for laser therapy) and nephropathy (incidence of albuminuria) persisted despite a narrowing of the HbA1c levels in the two groups.

The Kumamoto Trial,[22] which included 110 patients with type 2 DM, showed that intensive therapy with multiple daily injections (preprandial, regular, and bedtime intermediate acting insulin) compared with once or twice daily insulin injections decreased HbA1c from 9.4% to 7.1%. In addition, two-step progression of retinopathy decreased by 69%, nephropathy progression decreased by 70%, and nerve conduction velocities improved, supporting the efficacy of intensive therapy.

The UK Prospective Diabetes Study (UKPDS) Group [23,24] evaluated 5,102 patients with type 2 DM. Patients using intensive treatment (metformin;[23] sulphonylureas or insulin [24]) versus conventional treatment had lower average HbA1c (7.0% vs 7.9%) and 12-year risk reductions of 27% for retinal photo coagulation, 33% for microalbuminuria, and 74% for doubling of creatinine levels. These results further support the importance of intensive therapy in reducing the microvascular complications of diabetes.

Hypertension control has been shown to reduce the risk for both retinopathy and nephropathy. The Hypertension and Diabetes Study,[25,26] which was part of the UKPDS, enrolled 1,148 patients with type 2 DM and coexisting hypertension. Patients in the tight-control group had a blood pressure goal of <150/85 mm Hg on treatment. They were randomized to either captopril (angiotensin-converting enzyme [ACE] inhibitor) or atenolol (beta blocker). The comparator group had a higher blood pressure goal of <180/105 mm Hg; they were not randomized to the active treatments.

On average, patients in the tight-control group maintained an average blood pressure of 144/82 mm Hg versus 154/87 mm Hg in the comparator group. After 9 years of follow-up, tight control resulted in a 35% reduction in retinal photo coagulation (P <0.025), a 34% reduction in two-step deterioration of retinopathy, and a 47% risk reduction in visual acuity deterioration by three lines in the early treatment of diabetic retinopathy study (ETDRS) chart (P <0.005).[26]

The Euclid Trial,[27] which included 354 normotensive patients with type 1 diabetes aged 20 to 59 years, demonstrated that lisinopril treatment resulted in a 50% reduction in retinopathy progression, 73% reduction in 2-grade retinopathy progression, and an 82% reduction in development of proliferative retinopathy.

Several studies have assessed the effects of hypertension control on nephropathy in patients with type 1 and type 2 DM have been performed assessing effects. A 1983 study [28] showed that effective blood pressure control in patients with diabetes and nephropathy decreased albumin excretion rate by 50% and slowed the rate of GFR decline from 0.29 to 0.1 mL/min/month.

A 2001 meta-analysis [29] of 12 trials demonstrated that ACE inhibitors can delay progression to overt nephropathy by 62% in patients with type 1 CM with microalbuminuria. Many of these patients also experienced decreased albumin excretion rates. No studies in patients with type 1 DM have shown that starting ACE inhibitors when the albumin excretion rate is normal delays the development of microalbuminuria.

The Collaborative Study Group [30] studied the effect of an ACE inhibitor (captopril) in 409 patients with type 1 DM with overt nephropathy (protein excretion >500 mg/d and creatinine <2.5 mg/dL). Creatinine doubled in 12.1% of the patients receiving captopril and in 21.3% of patients receiving placebo (a 48% reduction in risk).

Several studies in patients with type 2 DM with microalbuminuria—with or without hypertension—have found that ACE inhibitors can delay progression to overt nephropathy, decrease the albumin excretion rate, and diminish the decline in GFR. Another study demonstrated that in patients with type 2 DM who were normotensive and normoalbuminuric, treatment with enalapril attenuated the increase in the albumin excretion rate and decreased the likelihood of development of microalbuminuria (a 12.5% risk reduction). In other studies in patients with type 2 DM, there is a slowing of progression of microalbuminuria to overt nephropathy when angiotensin II-receptor blockers are administered.


Glucose, BP control. Based on these studies, the ADA recommends a preprandial plasma glucose goal of 80 to 130 mg/dL and a postprandial goal of <180 mg/dL. The ADA goal for HbA1c is <7% (normal HbA1c is <6%) and the BP goal is <140/90 mm Hg.[31]

The AACE recommends preprandial glucose targets of <110 mg/dL and <140 mg/dL postprandial.[9] The HbA1c goal is <6.5% and the BP goal of <130/85 mm Hg. Both the ADA and AACE recommend HbA1c measurements every 3 months.

Self-administered glucose testing in patients with type 1 DM or in pregnant women with diabetes is recommended at least three times a day. The frequency of glucose monitoring for type 2 DM should be sufficient to facilitate achievement of the glucose goals.

In hypertensive patients with microalbuminuria or albuminuria, therapy with ACE inhibitors or angiotensin II-receptor blockers should be strongly considered. The UKPDS found that intensive blood pressure control decreased microvascular complications by 37% with both ACE inhibitors and beta blockers.[26]

Retinopathy. Patients with type 1 DM should have an initial dilated and comprehensive eye exam within 5 years of the onset of diabetes. Patients with type 2 DM should have an eye exam shortly after diagnosis. Patient with either type 1 or type 2 DM should have subsequent eye exams annually, performed by an ophthalmologist or optometrist knowledgeable and experienced in diagnosing retinopathy.

Visual loss in nonproliferative diabetic retinopathy occurs primarily through development of macular edema. When clinically significant macular edema is present, intraviteral anti vascular endothelial growth factor (VGEF) or focal laser photocoagulation are initial treatment options.

Once retinopathy is established, the best treatment to prevent blindness in those with high-risk and severe proliferative retinopathy is laser photocoagulation. The Diabetic Retinopathy Study found that a 50% reduction in severe visual loss could be achieved by using photocoagulation to treat eyes with neovascularization associated with vitreous hemorrhage or neovascularization on or near the optic disc, and for eyes with proliferative retinopathy or very severe nonproliferative retinopathy.[32,33] Anti-VGEF inhibitors can be used as adjunct therapy to prevent photocoagulation for selected cases of diabetic retinopathy. The Diabetic Retinopathy Clinical Research Network found that 0.5 mg intravitreous ranibizumab was noninferior to panretinal photocoagulation at 2 years in regards to visual acuity outcomes.[34] Long-term data, however, are not available. If vitreous hemorrhage occurs and does not resolve, vitrectomy may restore vision.

Nephropathy. Early nephropathy is associated with microalbuminuria, hypertension, and, possibly, elevated creatinine. First-line therapy is directed toward controlling hypertension. Generally, ACE inhibitors are first-line agents. Patients who develop a severe cough, a common side effect of ACE inhibitors, can be switched to an angiotensin II-receptor blocker. These agents have shown similar efficacy at decreasing microalbuminuria, lowering blood pressure, and preventing worsening renal function. Some calcium channel blockers (diltiazem and verapamil) have been shown to decrease microalbuminuria and may be added to the medications, if necessary. If creatinine increases above 2 or 3 mg/dL, ACE inhibitors should be avoided because overt renal failure can result, which can lead to a need for dialysis or kidney transplant.

Neuropathy. The Diabetes Control and Complications trial found some improvement in neuropathy with intensive diabetes control.[20] If this is not successful, further treatment should focus on analgesia. The most common neuropathy is bilateral distal polyneuropathy. Increasing doses of tricyclic antidepressants, gabapentin, phenytoin, carbamazepine, and benzodiazepines have been used with varying degrees of success. Several agents have shown promise for restoring the structural nerve damage that can cause neuropathy including laminin B2, immunoglobulin FI and FII, nerve growth factor, insulin, and neurotrophin-3. Gastroparesis is treated with metoclopramide.

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Management: Macrovascular Risks

Patients with diabetes are at increased risk for the macrovascular complications of CVD. Compared with a nondiabetic population, patients with diabetes have a two- to four-fold increased risk of CVD, and more than half of patients with diabetes die from CVD complications.[35,36] The increased CVD risks include coronary ischemia, stroke, MI, and angina pectoris. Guidelines from the United States and Europe consider type 2 DM to be a CVD equivalent, thereby elevating it to the highest category.[36,37]

Table 3 lists the common CVD risk factors associated with diabetes and recommended therapeutic goals. Practitioners should note that not all patients with diabetes have an elevated risk of a cardiac event, so some discretion may be used with the guidelines.

Table 3. Goals for managing CVD risk factors in patients with diabetes.
Risk Factor Goal of Therapy
  LDL cholesterol, pts with CVD+DM LDL <70 mg/dL
  LDL cholesterol level elevated LDL <70 mg/dL
  Triglyceride level 200-499 mg/dL Non-HDL cholesterol level <130 mg/dL
  HDL cholesterol level <40 mg/dL Raise HDL (no specific goal)
Hypertension BP <140/90 mmHg (ADA, JNC 8)
Prothrombotic state (elevated plasminogen activator inhibitor) Low-dose aspirin therapy (patients with CVD and other risk factors)
Hyperglycemia HbA1c <7%
Overweight (BMI 25-29.9 kg/m2)
Obese (BMI ≥30 kg/m2)
Decrease BMI to healthy weight
Physical inactivity Exercise prescription depending on patient's status
Cigarette smoking Complete cessation
Adverse nutrition Achieve, maintain goals for plasma glucose, lipids, BP

Abbreviations: ADA=American Diabetes Association; BMI=body mass index; BP=blood pressure; CVD=cardiovascular disease; HDL=high-density lipoprotein; JNC VI=Sixth Report of the Joint National Committee on Prevention, Evaluation, and Treatment of High Blood Pressure; LDL=low-density lipoprotein.

Adapted from ADA and JNC 8.[31, 42].


Guidelines for the management of dyslipidemia have been published by the National Cholesterol Education Program and by expert panels from the AACE, ACP, ADA, ACC, and AHA. The guidelines are generally consistent in recommending aggressive lipid-lowering management in diabetes.

The proposed LDL cholesterol level targets are as follows:[37,39]

  • The LDL cholesterol level is <100 mg/dL for any patient with diabetes.
  • If the LDL cholesterol level is <100 mg/dL but triglyceride (and very LDL [VLDL] cholesterol) levels are elevated, then the non-high-density lipoprotein (HDL) cholesterol level should be <130 mg/dL.
  • For patients at very high risk, such as diabetic patients with a prior MI, the recommended LDL cholesterol level is <70 mg/dL; the non-HDL cholesterol level is <100 mg/dL.
  • Patients who have an LDL cholesterol level <100 mg/dL without medication should be treated to achieve a >30% reduction in the LDL cholesterol level.

These guidelines are based on findings from lipid-lowering trials that included diabetic patients and were confirmed by subsequent trials.[37]

Post-hoc analyses of diabetic patients who were included in lipid-lowering trials have supported the notion that these patients have comparable relative reductions (or perhaps greater absolute reductions) in the risk for CVD events than their nondiabetic counterparts. These data are summarized in the ACP guidelines.[40] The ADA and AHA guidelines [19] suggest an LDL cholesterol level target of <100 mg/dL for patients with diabetes and an optional target of <70 mg/dL for patients with diabetes and CVD.

In addition, these guidelines recommend 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 <130 mg/dL, with an optional target of <100 mg/dL. These guidelines are still recommended by the AACE.

The ACC/AHA guidelines also recommend that patients with diabetes aged 40 to 75 years and an LDL level of 70 to 189 mg/dL should be treated with a high-intensity statin without a target cholesterol level.[41]


In patients with diabetes, large clinical trials have demonstrated favorable effects of BP control on reducing CVD risks. The ADA guidelines recommend BP targets of 140/90 mm Hg.[31, 42] Multidrug regimens (often three or more drugs) are usually required to reach BP targets. Based on studies in patients with diabetes showing favorable cardiovascular results with the ACE inhibitors ramipril (HOPE [43]) and perindopril (EUROPA study [44]), these agents should be considered part of initial therapy in patients with hypertension and type 2 DM.

The large ONTARGET study (N=25,620; 38% with diabetes) evaluated CVD outcomes in three treatment arms: ramipril, telmisartan, and both drugs combined.[45] There were no differences among the three arms. The beneficial effects could not be entirely attributed to BP reduction in these trials. The ACCORD trial showed no benefit in decreasing BP <120 mm Hg versus <140 mm Hg.[46]

Glycemic Control

Intervention trials have shown a somewhat modest relationship between glycemic control and CVD risk. In the UKPDS trial, an HbA1c reduction of 0.9% was associated with a 14% reduction in the MI risk (P = .052) in the intention-to-treat analyses and a 16% reduction for every 1% HbA1c level change in a post hoc observational analysis.[24, 47] The metformin arm in obese patients in the UKPDS had a 39% reduction in MI risk compared with the conventional arm (P = .010).[23] The ACCORD (N=10,251) and ADVANCE (N=11,140) trials did not demonstrate beneficial effects of intensive control (HbA1c <7.0%) on CVD events.[48,49]

The Diabetes Control and Complications Trial (DCCT) showed no CV benefits from intensive glucose-control therapy during the initial trial.[50] The Epidemiology of Diabetes Interventions and Complications (EDIC) study, the DCCT long-term follow-up study, found a 42% reduction in risk of any cardiac event during the duration of the DCCT/EDIC study and a 57% reduction in nonfatal myocardial infarction or death from CVD during a 17-year follow-up of the patients in the DCCT.[51]

Two studies published in 2012 suggest that patients with a BMI ≥35 may benefit from gastric bypass surgery as treatment for obesity and diabetes. Mingrone et al [52] found that in patients with a BMI ≥35, 95% of those treated with biliopancreatic diversion and 75% of those treated with gastric bypass had remission of diabetes. Schauer et al [53] found that in obese patients with type 2 DM, the percentage who achieved glycemic control (HbA1c ≤6% at 1 year) was statistically significantly greater in those treated with Roux-en-Y gastric bypass (42%) or sleeve gastrectomy (37%) compared with patients medically managed (12%).

Recommendation. A patient with diabetes should be referred to an endocrinologist if targets for glycemic control cannot be achieved or if the patient is experiencing severe hypoglycemia. It is important to refer patients early in the disease stage to help them avoid long-term complications. Also, patients who develop complications should be referred to an endocrinologist to see if glycemic control can be improved or simply to treat the complications.


Aspirin therapy is recommended in the ADA guidelines for primary prevention of CVD in patients with diabetes.[8, 54] Aspirin is recommended for all adults with a 10-year Framingham CVD risk >10%, for most men ≥50 years old, for most women ≥60 years old, and for those with any of the following risk factors: tobacco use, microalbuminuria, family history of premature CVD, hypertension, and dyslipidemia. Aspirin is recommended for adults with a 10-year risk of a coronary event below 5%, for men younger than 50, and for women younger than 60 with no additional risk factors.

In men aged ≥50 years and in women aged ≥60 years with type 1 or type 2 DM plus an additional risk factor, aspirin should be used for secondary prevention. Aspirin should be used in combination with clopidogrel for up to 1 year in these patients following acute coronary syndrome.


The watchword of the ADA is that diabetes is a serious disease associated with significant morbidity and mortality related to microvascular and macrovascular complications. Careful screening for these complications provides clinicians with opportunities to reduce the risk for their development and 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 has been shown to reduce the CVD risk in these patients. 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 Points

  • Diabetes is a leading cause of retinopathy, nephropathy, and neuropathy.
  • Diabetes increases the CVD risk by 2- to 5-fold.
  • Glycemic control is associated with a reduced risk for both microvascular and macrovascular complications of diabetes.
  • Treatment of CVD risk factors, especially dyslipidemia, is associated with a reduced risk for CVD events.
  • Early detection of microvascular complications and implementation of appropriate treatment strategies, such as laser therapy (retinopathy), ACE inhibitors or angiotensin receptor blockers, and proper footwear (neuropathy), can reduce the risk for adverse outcomes from these complications.
  • Blood pressure goals for patients with diabetes should be <140/90 mm Hg.
  • Goals for LDL are <100 mg/dL in patients with diabetes; the LDL goal is <70 mg/dL for patients with concomitant coronary heart disease or in patients 40 to 75 years old treated with high-intensity statin.

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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 Association of Diabetes Educators. Position statement. Diabetes education and public health. Diabetes Educ 2000; 26:607–609.
  • Grundy SM, Howard B, Smith S Jr, et al. Prevention Conference VI: Diabetes and Cardiovascular Disease: Executive summary: Conference proceeding for health care professionals from a special writing group of the American Heart Association. Circulation 2002; 105:2231–2239.
  • Krauss RM, Eckel RH, Howard B, et al. AHA Dietary Guidelines: Revision 2000: A statement for health care professionals from the Nutrition Committee of the American Heart Association. Circulation 2000; 102:2284–2299.
  • Lebovitz HE, Austin MM, Blonde L, et al. ACE/AACE consensus conference on the implementation of outpatient management of diabetes mellitus: consensus conference recommendations. Endocr Pract 2006; 12:(Suppl 1)6–12.
  • Lichtenstein AH, Appel LJ, Brands M, et al. Diet and lifestyle recommendations revision 2006: a scientific statement from the American Heart Association Nutrition Committee. Circulation 2006; 114:82–96.
  • Pugliese G. Updating the natural history of diabetic nephropathy. Acta Diabetol 2014; 51:905-915.
  • Smith SC Jr, Allen J, Blair SN, et al. AHA/ACC guidelines for secondary prevention for patients with coronary and other atherosclerotic vascular disease: 2006 update: endorsed by the National Heart, Lung, and Blood Institute. Circulation 2006; 113:2363–2372.
  • The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. Sustained effect of intensive treatment of type 1 diabetes mellitus on development and progression of diabetic nephropathy: the Epidemiology of Diabetes Interventions and Complications (EDIC) study. JAMA 2003; 290:2159–2167.


This chapter is updated from two previous Disease Management chapters: "Diabetes Mellitus: Disease Management," by Byron J. Hoogwerf, MD, and "Microvascular Complications of Diabetes," by Robert S. Zimmerman, MD.

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Robert S. Zimmerman, MD, no disclosures.