Published: August 2010
The microvascular complications of diabetes encompass long-term complications of diabetes affecting small blood vessels. These classically have included retinopathy, nephropathy, and neuropathy. Retinopathy is divided into two main categories: nonproliferative retinopathy and proliferative retinopathy. Nonproliferative retinopathy can be recognized by development of microaneurysms, venous loops, retinal hemorrhages, hard exudates, and soft exudates. Proliferative retinopathy is defined as presence of new blood vessels with or without vitreous hemorrhage. Proliferative retinopathy represents a progression of nonproliferative retinopathy.
Diabetic nephropathy is defined as the presence of persistent proteinuria greater than 0.5 g/day. Overt nephropathy is characterized by progressive decline in renal function resulting in end-stage renal disease.
Neuropathy is a group of conditions characterized by nerve dysfunction. The condition is classified according to the nerves affected. The classification of neuropathy includes focal, diffuse, sensory, motor and autonomic neuropathy.
In patients with type 1 diabetes mellitus (T1DM), 13% have retinopathy at 5 years and 90% have retinopathy after 10 to 15 years. Twenty-five percent of type 1 diabetics develop proliferative retinopathy after 15 years of diabetes.1 Patients with type 2 diabetes mellitus (T2DM) taking insulin have a 40% prevalence of retinopathy at 5 years, and those taking oral hypoglycemic agents have a 24% prevalence. By 15 to 19 years of diabetes, the rates increase to 84% and 53%, respectively. Proliferative retinopathy develops in 2% of type 2 patients with less than 5 years of diabetes and in 25% with 25 or more years of diabetes.2 The prevalence of nephropathy in diabetes has not been determined. Thirty percent of patients with type 1 diabetes and 5% to 10% with type 2 diabetes become uremic.3 The prevalence of neuropathy as defined by loss of ankle jerk reflexes is 7% at 1 year of diabetes, increasing to 50% at 25 years4 for both T1DM and T2DM.
Microaneurysm formation is the earliest manifestation of diabetic retinopathy. Microaneurysms can form due to release of vasoproliferative factors, weakness in the capillary wall or increased intraluminal pressures. Microaneurysms can lead to increased vascular permeability, which can lead to macular edema and threatens central vision. Obliteration of retinal capillaries can lead to intraretinal microvascular abnormalities (IRMA). As capillary closure becomes extensive, intraretinal hemorrhages develop.
Proliferative retinopathy develops due to ischemia and release of vasoactive substances that stimulate new blood vessel formation as a progression of nonproliferative retinopathy. These vessels erupt through the surface of the retina and grow on the posterior surface of the vitreous. These vessels are very friable and can lead to vitreous hemorrhages. The vitreous can then contract, leading to retinal detachment.
The pathophysiology of neuropathy is complex. Diabetes is associated with dyslipidemia, hyperglycemia, low insulin, and growth factor abnormalities. These abnormalities are associated with glycation of blood vessels and nerves. In addition, autoimmunity can affect nerve structure. Trauma and neuroentrapment can lead to structural nerve damage, including segmental demyelination, axonal atrophy or loss, and progressive demyelination. Several agents, including laminin B2, insulin-like growth factor (IGF) 1 and 2, nerve growth factor (NGF), insulin, and neurotrophin 3 (NT-3) are potential growth factors that might restore nerve function.
Diabetic nephropathy results from increased glomerular capillary flow, which leads to increased extracellular matrix production and endothelial damage. This leads to increased glomerular permeability to macromolecules. Mesangial expansion and interstitial sclerosis ensues, resulting in glomerular sclerosis.
Symptoms of retinopathy are minimal until advanced disease ensues with loss or blurring of vision. Signs of nonproliferative retinopathy include microaneurysm, venous loops, retinal hemorrhages, hard exudates, and soft exudates. Proliferative retinopathy includes new vessels in the eyes or vitreous hemorrhage.
The earliest sign of nephropathy is hypertension. Development of hypertension often coincides with the development of microalbuminuria. As nephropathy worsens, patients can develop edema, arrhythmias associated with hyperkalemia, and symptoms related to renal failure.
Signs and symptoms of neuropathy depend on the type of neuropathy. Most commonly patients develop symptomatic distal polyneuropathy. Signs include depression or loss of ankle jerks and vibratory sensation, with hyperalgesia and calf pain in some patients. The deficit is in a stocking-and-glove distribution. Wasting of the small muscles of hands and feet can also occur.
Patients may present with focal neuropathies either due to 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. It begins with pain followed by severe weakness and spreads from a unilateral distribution to a bilateral one. It resolves spontaneously in 18 to 24 months.
The diagnosis of nephropathy is initially based on development of microalbuminuria. Microalbuminuria is defined as an albumin excretion rate of 20 to 200 μg/min. Because the average daily albumin excretion rate can vary by 40%, it is recommended that three urine collections be made over several weeks before making this diagnosis. Overt nephropathy is defined as an albumin excretion rate greater than 300 mg in 24 hours. This is associated with a linear decline in glomerular filtration rate (GFR) ranging from 0.1 to 2.4 mL/min/month.
Diagnosis of retinopathy is based on finding the diagnostic signs of retinopathy on eye examinations as discussed earlier.
The diagnosis of neuropathy is based on presence of weakness or diminished sensation as described earlier. These findings can be confirmed with nerve conduction studies.
Prevention is the primary therapy for microvascular complications of diabetes. The 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 Study1, 2, 6-10 demonstrated that in diabetics younger than 30 years and those older than 30 years treated with oral hypoglycemic agents or insulin, baseline hemoglobin A1c (HbA1c) level correlated with the incidence of retinopathy, progression of retinopathy, and progression of proliferative retinopathy.
The Diabetes Control and Complications Trial11 (DCCT) enrolled 1441 people with type 1 diabetes. Of these, 726 had no retinopathy, had normal albumin excretion, and had had diabetes for less than 5 years. The other 715 had mild-to-moderate background retinopathy with normal albuminuria or microalbuminuria at baseline.
The subjects received intensive therapy or conventional treatment. The intensive treatment was either given with insulin pumps or multiple daily injections (three or more injections per day.) The insulin dosage was guided by self-monitoring of blood glucose three or four times per day. The participants were seen every month.
The conventional group received no more than two shots per day. Urine and blood glucose were monitored up to two times per day. They had clinic visits every 2 or 3 months over an average of 6.5 years. The average HbA1c was 9.1% in the conventional group and 7.2% in the intensively treated group throughout the study. Risk reduction was 70% for clinically important sustained retinopathy, 56% for laser photocoagulation, 60% for sustained microalbuminuria, 54% for clinical grade nephropathy, and 64% for clinical neuropathy. Four years after the close of the DCCT, HbA1c levels in the two groups narrowed to 8.2% in the conventional treatment group and 7.9% in the intensive treatment group. Retinopathic events including proliferative retinopathy, macular edema, and need for laser therapy were 74%, 77%, and 77% lower, respectively, in the intensively treated group. Incidence of microalbuminuria was 53% lower and albuminuria was 86% lower in the intensively treated group.12
In the Kumamato trial13 in 102 patients with T2DM, intensive therapy with multiple daily injections (preprandial, regular, and bedtime intermediate-acting insulin) compared with once or twice daily insulin injections resulted in a decrease in HbA1c from 9.4% to 7.1%. Two-step progression of retinopathy decreased 69%, nephropathy progression decreased 70%, and nerve conduction velocities improved.
The United Kingdom Prospective Diabetes Study (UKPDS)14, 15 evaluated 5102 patients with T2DM. The study maintained an average HbA1c of 7.9% in the conventional treatment group compared to 7% in the intensive treatment group. There was a 27% risk reduction for retinal photocoagulation at 12 years, 33% risk reduction at 12 years for microalbuminuria, and 74% risk reduction for doubling of creatinine at 12 years.
Blood pressure control has been shown to reduce the risk for both retinopathy and nephropathy. The Hypertension and Diabetes Study16, 17 was part of the UKPDS study. The subjects were 1148 patients with T2DM and coexisting hypertension. Tight-control subjects were given a blood pressure goal of lower than 150/85 mm Hg. Most patients were treated with captopril or atenolol. The control group was given a blood pressure goal of lower than 180/105 mm Hg. On average, the tight-control group averaged 144/82 mm Hg and the control group averaged 154/87 mm Hg. The tight-control group had a 35% reduction in retinal photocoagulation (P < 0.025), 34% reduction in two-step deterioration of retinopathy, and 47% risk reduction in three-line deterioration in the ETDRS chart (P < 0.005) over 7.5 years.
The Euclid (EUrodiab Controlled trial of Lisinopril in Insulin-Dependent Diabetes) study18 in 354 normotensive type 1 diabetics aged 20 to 59 years demonstrated that lisinopril treatment resulted in a 50% reduction in retinopathy progression, 73% reduction in two-grade retinopathy progression, and an 82% reduction in development of proliferative retinopathy.
Several studies have been performed in T1DM and T2DM patients to assess the effects of blood pressure control on nephropathy. Parving19 demonstrated that blood pressure control in diabetes with nephropathy decreased the albumin excretion rate by 50% and the rate of decline of GFR from 0.29 to 0.1 mL/min/month. A recent meta-analysis20 demonstrated that angiotensin-converting enzyme (ACE) inhibitors can delay progression to overt nephropathy by 62% in type 1 diabetics with microalbuminuria. Many also decreased their albumin excretion rate. No studies in T1DM patients show that starting ACE inhibitors when albumin excretion rate is normal delays the development of microalbuminuria.21-31 In overt nephropathy, Lewis32 studied 409 type 1 diabetics with protein excretion greater than 500 mg/day and creatinine less than 2.5 mg/dL. Creatinine doubled in 12.1% of the patients receiving captopril and 21.3% in the patients receiving a placebo (a 48% reduction in risk.)
In type 2 diabetic patients with microalbuminuria with or without hypertension, several studies have found that ACE inhibitors delay progression to overt nephropathy, decrease albumin excretion rate, and diminish decline in GFR.33-40 Only one study has demonstrated that in type 2 diabetics who are normotensive and normoalbuminuric, enalapril attenuates the increase in albumin excretion rate and decreases the likelihood of development of microalbuminuria (a 12.5% risk reduction).41 Several studies42-45 using angiotensin II receptor blockers have been published.36-39 These studies show that in T2DM, there is a slowing of progression of microalbuminuria to overt nephropathy.
Based on these studies, the American Diabetes Association (ADA)46 recommends a goal preprandial plasma glucose of 70 to 130 mg/dL. The postprandial glucose goal is lower than 180 mg/dL. Normal HbA1c is less than 6%. Goal is less than 7%. The ADA target for blood pressure is less than 130/80. The American Association of Clinical Endocrinology recommends preprandial glucose targets of less than 110 mg/dL, postprandial glucose less than 140 mg/dL, and HbA1c less than 6.5%.47 They also recommend a blood pressure goal of lower than 130/85. HbA1c measurements are suggested every 3 months. Blood sugar testing in type 1 diabetics or pregnant women with diabetes is suggested at least three times a day. The frequency of glucose monitoring for type 2 diabetics is not known but should be sufficient to facilitate achievement of the glucose goals.
In hypertensive patients with microalbuminuria or albuminuria, ACE inhibitors or angiotensin II receptor blockers should be strongly considered. Patients with T1DM should have an initial dilated and comprehensive eye examination within 3 to 5 years of the onset of diabetes. Patients with T2DM should have an eye examination shortly after diagnosis. Both type 1 and type 2 diabetics should have subsequent eye examinations annually; these should be performed by an ophthalmologist or optometrist knowledgeable and experienced in diagnosing retinopathy.
Once retinopathy is established, the best treatment to prevent blindness in those with proliferative retinopathy is laser photocoagulation.48-52 The Diabetic Retinopathy Study found that a 50% reduction in severe visual loss could be achieved by treating eyes with neovascularization associated with vitreous hemmorhage or neovascularization on or near the optic disc and eyes with proliferative retinopathy or very severe nonproliferative retinopathy.48-52 If vitreous hemorrhage occurs and does not resolve, vitrectomy can be performed to restore vision.
Early nephropathy is associated with microalbuminuria, hypertension, and possible elevation in creatinine. First-line therapy is directed toward controlling the hypertension. Generally, ACE inhibitors are agents of first choice. If patients develop a cough, angiotensin receptor blockers have shown similar efficacy at decreasing microalbuminuria, lowering blood pressure, and preventing worsening renal function. Certain calcium channel blockers (cardizem and verapamil) have been shown to decrease microalbuminuria and may be added to these medications if necessary. If creatinine increases above 2 to 3 mg/mL, ACE inhibitors should be avoided because overt renal failure can result. If renal failure develops, treatment with dialysis or kidney transplantation should be considered.
The DCCT found some improvement in neuropathy with intensive diabetes control. If this is not successful, further treatment of neuropathy is centered around pain control. The most common neuropathy is bilateral distal polyneuropathy. Increasing doses of tricyclic antidepressants, neurontin, dilantin, tegretol, and benzodiazepines have been used with varying degrees of success. Gastroparesis is treated with metoclopramide (Reglan).
Patients with diabetes should be referred to an endocrinologist if targets for glycemic control cannot be achieved or if patients are experiencing significant hypoglycemia. It is important to refer early to help patients avoid long-term complications of diabetes. Patients who are developing complications of diabetes should be referred to an endocrinolgosit to see if any further treatments are available to improve glycemic control or to treat the complications.