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DefinitionPrevalencePathophysiologySigns
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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. Non-proliferative retinopathy and proliferative
retinopathy. Non-proliferative 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 non-proliferative retinopathy.
Diabetic nephropathy is defined as the presence of persistent proteinuria >0.5 gms/24 hours. Overt nephropathy is characterized by progressive decline in renal function resulting in end stage renal disease. Neuropathy is a heterogenious condition that is associated with nerve pathology. The condition is classified according to the nerves affected. The classification of neuropathy includes focal, diffuse, sensory, motor and autonomic neuropathy. |
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In Type 1 diabetic patients, 13% have retinopathy at 5 years and 90% have retinopathy after 10-15 years. Twenty-five percent of Type 1 diabetics develop proliferative retinopathy after 15 years of diabetes.1 Type 2 diabetics taking insulin have a 40% prevalence of retinopathy at 5 years, while those on oral hypoglycemic agents have a 24% prevalence. By 15 -19 years of diabetes, the rates increase to 84% and 53% respectively. Proliferative retinopathy develops in 2% of Type 2 patients with <5 years of diabetes and 25% with 25 or more years of diabetes.2 The prevalence of nephropathy in diabetes has not been determined. Thirty percent with IDDM and 5-10% with NIDDM become uremic.3 The prevalence of neuropathy defined by loss of ankle jerk reflexes is 7% at 1 year increasing to 50% at 25 years4 for both type 1 and type 2 diabetes. |
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PATHOPHYSIOLOGY |
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Microaneurysm formation
is the earliest manifestation of diabetic retinopathy. Microaneurysms
may form due to release of vasoproliferative factors, weakness in the
capillary wall or increased intra-luminal pressures. Microaneurysms can
lead to vascular permeability. Vascular permeability in the macula 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. Diabetic nephropathy results from increased glomerular capillary flow which results in increased extracellular matrix production and endothelial damage. This leads to increased glomerular permeability to macromolecules. Mesangial expansion and interstitial sclerosis ensues leading to glomerular sclerosis. |
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Symptoms of retinopathy are minimal until advanced disease ensues with loss or blurring of vision. Signs of non proliferative 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 signs 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/or symptoms related to renal failure. Signs and symptoms of neuropathy are dependent on the type of neuropathy that develops. 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 glove distribution. Waisting of the small muscle 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 unilateral to bilateral. It resolves spontaneously in 18-24 months. |
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DIAGNOSIS |
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The diagnosis of nephropathy is initially based on development of microalbuminuria. Microalbuminuria is defined as an albumin excretion rate 20-200 ug/min. Because the average daily albumin excretion rate varies in normals and diabetics by 40%, it is recommended that 3 urine collections over several weeks be made 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 0.1-2.4 ml/min/month. Diagnosis of retinopathy is based on finding the diagnostic signs of retinopathy on eye exams as discussed under signs above. The diagnosis of nephropathy is based on finding either weakness or diminished sensation as described above. These findings can be confirmed with nerve conduction studies. |
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The primary therapy is prevention for the microvascular complications of diabetes. 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 Study1,2,6-10 demonstrated that in both diabetics younger than 30 years and those over 30 years treated with oral hypoglycemic agents or insulin, baseline Hb A1C level correlated with the incidence of retinopathy, progression of retinopathy, and progression of proliferative retinopathy. The Diabetes Control and Complications Trial11 (DCCT) enrolled 1,441 people with type 1 diabetes. There were 726 that had no retinopathy, normal albumin excretion and diabetes for less than five years. There were 715 that had mild-to-moderate background retinopathy with normal or micro-albuminuria 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 sugar 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 sugars were monitored no more than two times per day. They had clinic visits every two or three months over an average of 6.5 years. The average hemoglobin A1C 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 photo coagulation, 60% for sustained micro-albuminuria, 54% for clinical grade nephropathy, and 64% for clinical neuropathy. Four years after the close of the DCCT, hemoglobin A1C 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 in the intensively treated group. Incidences of micro-albuminuria was 53% lower and albuminuria, 86% lower in the intensively treated group.12 The Kumamato Trial13 demonstrated that in 102 patients with type 2 diabetes, 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 hemoglobin A1C 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 Study14,15 evaluated 5,102 patients with type 2 diabetes. Patients were treated with sulphonylureas or insulin in one study and another group was compared to these groups using metformin in a second study. The study maintained an average hemoglobin A1C of 7.9% in the conventional treatment group compared to 7% in the intensive treatment group. There was a 27% risk reduction for retinal photo coagulation at 12 years, 33% risk reduction at twelve years for micro-albuminuria, and 74% risk reduction for doubling of creatinine at twelve 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. There were 1,148 patients with type 2 diabetes and coexisting hypertension that were studied. Tight control subjects were given a blood pressure goal of <150/85 mm Hg on treatment. Most patients were treated with captopril or Atenolol. The control group was given a blood pressure goal <180/105 mm Hg. On average, the tight control group averaged 144/82 mm Hg of the control group averaged 154/87 mm Hg. Tight control resulted in 35% reduction in retinal photo coagulation (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 Trial18 in 354 type 1 diabetics aged 20-59 who were normotensive 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 assessing effects of blood pressure control in type 1 and type 2 diabetes have been performed assessing effects on nephropathy. Parving19 demonstrated that blood pressure control in diabetes with nephropathy decreased albumin excretion rate by 50% and the rate of decline of GFR from 0.29 to 0.1 milliliter per minute per month. A recent Meta Analysis20 involving multiple studies21-31 demonstrated that ACE inhibitors can delay progression to overt nephropathy by 62% in type 1 diabetics with micro-albuminuria. Many also decreased their albumin excretion rate. No studies in type 1 patients show that starting ACE inhibitors when albumin excretion rate is normal delays the development of micro-albuminuria. In overt nephropathy Lewis32 studied 409 type 1 diabetics with protein excretion greater than 500 milligrams per day and creatinine less than 2.5. 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 micro-albuminuria 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 that enalapril attenuates the increase in albumin excretion rate and decreases the likelihood of development of micro-albuminuria (a 12.5% risk reduction).41 Several studies42-45 using angiotensin II receptor blockers have recently been published.36-39 These studies show that in type 2 diabetes, there is a slowing of progression of micro-albuminuria to overt nephropathy. Management: Based on these studies, the American Diabetes Association (ADA) recommends46 that goal preprandial plasma glucose is 90-130 mg/dL. Post-prandial glucose goal is <180 mg/dl. Normal hemoglobin A1C is less than six. Goal is less than seven. The ADA target for blood pressure is <130/80. The American Association of Clinical Endocrinology recommends preprandial glucose targets of <110, post-prandial, <140 and HbA1C < to 6.5.47 They also recommend blood pressure goal of <130/85. Hemoglobin A1C measurements are suggested every three months. Blood sugar testing in type 1 diabetics or pregnant women with diabetes are 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 micro-albuminuria or albuminuria, 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.17 Patients with type 1 diabetes should have an initial dilated and comprehensive eye exam within three to five years of the onset of diabetes. Patients with type 2 diabetes should have an eye exam shortly after diagnosis. Both type 1 and type 2 diabetics should have subsequent eye exams annually; which 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 photo-coagulation.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 non-proliferative retinopathy.48-52 If vitreous hemorrhage occurs and does not resolve vitrectomy can be performed to restore vision. Early nephropathy is associated with micro albuminuria, 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 and lowering blood pressure and preventing worsening renal function. Certain calcium channel blockers (cardizem & verapamil) have been shown to decrease microalbuminuria and may be added to the above medications if necessary. If creatinine increases above 2 or 3, ACE inhibitors should be avoided since overt renal failure can result. If renal failure develops, treatment with dialysis or kidney transplant should be considered. The diabetes control and complications trial 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 reglan. |
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Patients with diabetes should be referred to an endocrinologist if targets for glycemic control cannot be achieved or 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. |
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