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OD’s role in diabetes management goes beyond eye exam

This condition can affect nearly every organ in the body. Education and appropriate referral are vital components of care.

by Anthony A. Cavallerano, OD

This course is jointly sponsored by PCON, The State University of New York State College of Optometry and Vindico Medical Education. It is COPE-approved for 2 continuing education credits.

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Diabetes mellitus (DM) is a complex, multisystem disease that has reached epidemic proportions over the last decade. The increased prevalence of type 2 diabetes has created a national and worldwide health care burden of epic proportions.

The microvascular and macrovascular complications from chronic hyperglycemia have been shown to have a significant impact on morbidity and mortality. As the number of diabetes cases increases, health care providers face formidable challenges in providing timely and systematic care to all diabetic patients.

Diabetic patients seeking care in a primary care optometric practice is increasingly more common, and optometrists play an important role in the overall management of the diabetic patient. This role is no longer strictly limited to comprehensive eye examination and monitoring. Patient education and referral for appropriate subspecialty treatment of ocular and systemic complications are important components to overall primary care.

The statistics

In the United States, 20.8 million children and adults – or 7% of the population – and nearly 200 million people worldwide have diabetes. While an estimated 14.6 million have been diagnosed, 6.2 million people – or nearly one-third – are unaware that they have the disease. About 1.2 million new cases of diabetes are reported each year.

Diabetes mellitus is the fifth leading cause of death in the United States and accounts for 10% to 14% of health care expenditures. Seventy percent of all deaths occurring from diabetes result from congestive heart failure.

Diabetes is the leading cause of new blindness in the working age population, and those with diabetes are 25 times more likely to be legally blind than nondiabetic people. Diabetes is responsible for 12,000 to 24,000 new cases of blindness every year in the United States and costs this country about $500 million annually in health care and related services. This condition is also the leading cause of lower extremity amputation, and the leading cause of end-stage renal disease in the United States.

Three classifications of diabetes

The American Diabetes Association recognizes three major classifications of diabetes. While other subcategories exist, it is type 1, type 2 and gestational diabetes that are most common. In type 1 diabetes, autoimmunity and circulating antibodies cause total destruction of the beta cells of the pancreas, resulting in a complete absence of insulin. Only 10% of those with diabetes have type 1. A putative trigger in genetically predisposed individuals produces the cascade of events resulting in type 1 diabetes.

Type 2 diabetes is more insidious, and individuals likely experienced a phase of impaired glucose tolerance that eventually leads to complete glucose intolerance. The mechanism of insulin resistance as a precursor in susceptible individuals along with obesity and the relation of the two factors to the development of type 2 diabetes has gained prominence in recent years.

Glucose is a simple sugar that is a basic requirement for cell energy. Insulin, the hormone secreted by the pancreas, promotes the uptake of glucose into cells, a necessary process for muscle, fat and liver cell function. After meals, glucose builds up in the bloodstream. The pancreas, sensing a high glucose level in the blood, may continue to excrete insulin, but it cannot be used effectively because adipose tissue prevents efficient uptake of glucose into cells. In this case, insulin may build up in the bloodstream, resulting in hyperinsulinemia along with hyperglycemia.

Loss of insulin production or efficiency may be genetic or secondary to high fat levels with fatty deposits in the pancreas. Both diet and lifestyle also appear to play a critical role.

Gestational diabetes mellitus (GDM) causes insulin resistance in pregnant women who have never had diabetes prior to their pregnancy. There are about 135,000 cases of GDM (about 4% of all pregnant women) in the United States each year, and GDM is a risk factor for developing diabetes later in life.

Affects all organs

Diabetes is a major cause of macrovascular and end organ microvascular complications and affects nearly every organ of the body. Chronic hyperglycemia, if left untreated, causes damage to the microcirculation of the retina, the kidney, the peripheral nerves and the brain. Eventually the larger vessels become involved, thus accounting for the increased risk of heart attack and stroke. Endothelial dysfunction is a prominent feature of insulin resistance, and compensatory hyperinsulinemia is associated with increased risk of cardiovascular disease.

Diabetes mellitus, along with hypertension, is the leading cause of renal failure in the United States, and there is also a strong correlation between nephropathy and retinopathy. Hypertension occurs in up to 68% of patients with type 2 diabetes, but there is evidence that hyperglycemia alone can play a critical role in renal microangiopathy, especially in those patients with long-standing diabetes.

Nearly 20% of diabetic patients develop some level of peripheral neuropathy after 5 years, and diabetes is the leading cause of nontraumatic lower extremity amputation in the United States and other industrialized countries. Patients are encouraged to see a podiatrist at least annually and to learn the process of self examination of the foot as part of their overall diabetic care.

Research, evidence-based findings

Much of what we know about diabetes and the importance of glycemic control is the result of two landmark intervention studies conducted during the last two and a half decades. The Diabetes Control and Complications Trial (DCCT), conducted between 1983 and 1993, and the United Kingdom Prospective Diabetes Study conclusively demonstrated that end-stage organ complications are not inevitable; rather, intensive control of blood glucose levels, as shown by reduction of HbA1c readings, substantially reduces the risk of microvascular complications from type 1 and type 2 diabetes.

The DCCT enrolled more than 1,400 type 1 diabetic patients and followed them for an average of 6.5 years. The study compared conventional therapy for glycemic control, which at the time showed an HbA1c of 9.1% for the observation group, with intensive treatment. The cohort of patients with intensive therapy had an average HbA1c of 7.2% at the conclusion of the study. The relative risk reduction for developing microvascular complications was significant for the intensive therapy group compared to the conventional group for onset and progression of retinopathy and the need for laser surgery.

The United Kingdom Prospective Diabetes Study (UKPDS) established similar results among patients with type 2 diabetes. This 20-year multicenter prospective interventional trial recruited nearly 4,000 newly diagnosed diabetic people with a median age of 54 years then randomized them to receive intensive glucose control and conventional control. Nearly 40% of the patients had retinopathy at baseline, a significant finding that indicates that the disease process was ongoing long before the actual diagnosis was made. In fact, the UKPDS predicted that the average type 2 subject probably had been hyperglycemic for an average of 4 to 7 years prior to the formal diagnosis of type 2 DM.

The UKPDS findings were prophetic given the recent epidemic of type 2 diabetes. Intensive glycemic control reduced the HbA1c from 7.9% to 7% over 10 years, resulting in a 34% reduction in progression of retinopathy, a 29% reduction in the need for retinal laser treatment and a 16% reduction in legal blindness. Additionally, there was an overall 25% reduction in the incidence of microvascular disease, including a 63% reduction in the onset of retinopathy, a 54% reduction in nephropathy and a 60% reduction in neuropathy.

Collectively, these clinical studies have provided the data that establishes current clinical management of diabetes and an acceptable target range for HbA1c of 6% to 8% for most diabetic patients.

Metabolic syndrome, prediabetes

Many patients with type 2 DM are obese; the inability to increase beta-cell insulin production results in diabetes. Some of these patients require oral hypoglycemic agents, but with sufficient weight loss, no treatment is necessary, and glucose levels can return to normal. In the progression from normal to abnormal glucose tolerance, postprandial glucose levels increase; however, insulin has insufficient capacity to promote cellular absorption of glucose from the blood.

Metabolic syndrome, a constellation of disorders that portent increased morbidity and mortality from cardiovascular disease, is often confused with prediabetes. Defined recently by the National Cholesterol Education Program Adult Treatment Panel, the syndrome includes abnormal glucose metabolism resulting from insulin resistance, hypertension and dyslipidemia.

The exact cause of metabolic syndrome remains unclear, but most researchers consider genetic framework and lifestyle choices to be important factors. Diet and level of physical activity appear to play an important role in determining who develops the syndrome. Obesity affects the body’s ability to use insulin efficiently, thus setting the stage for insulin resistance. In addition to abdominal obesity, the syndrome is also characterized by dyslipidemia and hypertension.

Prediabetes results from insulin resistance and is a condition that often precedes overt diabetes. Forty-one million adults in the United States can be classified as having prediabetes, a condition where blood glucose levels exceed normative values but are not quite high enough to be called diabetes.

The first indication might be impaired fasting glucose, a blood glucose level of 100 mg/dL to 125 mg/dL or impaired glucose tolerance (IGT). In IGT, the 2-hour postprandial levels are between 140 mg/dL and 200 mg/dL. Either or both of these levels are generally elevated long before increased blood glucose levels are detected. Prediabetes is asymptomatic and is part of the collection of features that make up metabolic syndrome.

Nonproliferative vs. proliferative DR

Virtually 100% of patients with type 1 diabetes of 20 years duration have diabetic retinopathy (DR), and 80% of those with type 2 diabetes of 15-year duration have some level of retinopathy. Alteration in blood flow results in microangiopathic changes in the retina. The earliest clinical signs are microaneurysms and punctate intraretinal hemorrhages (HM/a’s). Further reduction in blood flow results in hypoxia and regional dysfunction of the retinal microcirculation. Further alteration to retinal blood flow can lead to the appearance of cotton-wool spots and venous caliber changes, additional signs of retinal hypoxia.

Renal hypertensive retinopathy with macular edema, nerve fiber layer hemorrhages and cotton-wool spots in a 59-year old male with type 2 diabetes mellitus. Images: Cavallerano AA

Cotton-wool spots are highly correlated with retinal ischemia, are not specific to DR and may result from renal hypertension or other systemic complications. They do not directly predict progression of DR.

The superior temporal field in this patient’s left eye shows moderate intraretinal microvascular abnormalities.

Intraretinal microvascular abnormalities (IRMAs), newly formed or preformed vessels within the neurosensory retina, are a further indication of retinal ischemia. HM/a’s, venous beading and IRMA are sentinel lesions of DR and formally provide the criteria for diagnosis of level of diabetic retinopathy and predict progression of retinal complications.

With disease progression, the retina at this stage may be described as “featureless,” where small arteriole branches are reduced and the capillaries are pruned, with a lack of H/Ma and IRMA; by this time the retina often appears nonperfused. Identification of IRMA during a comprehensive examination is critical because 70% of neovascularization occurs in pre-existing areas of IRMA, typically at the border of perfused and nonperfused retina.

Proliferative DR involves the formation of new blood vessels that evolve from comparatively normal retinal vessels. A hypoxic retinal environment and the expression of angiogenic factors, principally vascular endothelial growth factor (VEGF), result in the proliferation of fragile vessels. New vessels on or above the surface of the retina extend into the vitreous, and accompanying fibrous proliferation exerts traction and resulting vitreous hemorrhage and ultimately a tractional retinal detachment.

Hemorrhage into the vitreous portends an ominous prognosis, and surgical intervention is often required in cases of nonresolving vitreous hemorrhage.

DR, DME staging, science

The Diabetic Retinopathy Study (DRS), a multicenter National Institutes of Health-sponsored clinical trial initiated in 1971, established conclusively the benefits of scatter or panretinal laser photocoagulation to treat proliferative DR. The DRS demonstrated that scatter panretinal photocoagulation reduced the risk of severe vision loss (5/200) by 50% in patients with proliferative DR at baseline.

In 1976 the Airlie House Classification of Diabetic Retinopathy established a group of standard color stereoscopic retinal photographs to document the appearance and degree of lesions of DR. Subsequently, the Early Treatment Diabetic Retinopathy Study (ETDRS) expanded the modified Airlie House Classification of DR.

Within the DRS and ETDRS, seven standard 30-degree field retinal photographs were used to diagnose the level of DR, with the standard photographs as reference to gauge the presence and degree of diabetic retinal lesions.

The ETDRS was a multicenter, randomized clinical trial designed to evaluate argon laser photocoagulation and aspirin treatment in the management of patients with nonproliferative or early proliferative DR. A total of 3,711 patients were recruited to be followed for a minimum of 4 years to provide long-term information on the risks and benefits of the treatments under study.

The three study arms aimed to determine the best time to initiate scatter laser treatment in DR; to determine the effectiveness of photocoagulation on visual function in patients with clinically significant diabetic macular edema; and to evaluate the effectiveness of 650 mg of aspirin in delaying or preventing retinopathy.

In 2001 an international committee was convened to revisit the system for classifying DR. This committee considered the Airlie House classification and, using findings from the ETDRS and Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR), devised a new system for classifying DR and diabetic macular edema. The new system is more clinically useful and understandable for eye care professionals; it also has more relevance for nonophthalmic professionals as well.

DME common cause for reduced vision

Diabetic macular edema (DME) remains the most common cause for reduced vision in the diabetic patient. Macular edema affects nearly 30% of patients with diabetes and clinically it is recognized that diabetic macular edema can be present with any level of DR.

A breakdown of the inner blood retinal barrier causes hyperpermeability of the retinal vasculature and the subsequent accumulation of intraretinal fluid, particularly in the inner and outer plexiform layers of the retina, resulting in retinal thickening. Hard exudates result from the resorption of the fluid elements from plasma.

Neovascularization elsewhere (NVE) in the superior temporal field and an inferior temporal preretinal hemorrhage can be seen in a patient with type 1 diabetes mellitus for 35 years.

Like cotton-wool spots, which are markers for retinal ischemia, hard exudates do not predict progression of DR but they are important markers for the presence of DME. Diabetic macular edema is considered clinically significant if it involves or threatens the center of the macula and thus poses a risk for vision loss.

Leakage from the compromised retinal vessels in the macular region may be either focal, discrete or diffuse. The visual prognosis is worse in cases that involve diffuse leakage because this form of DME is more difficult to treat.

The status of the vitreous plays an important role in cases involving DME. Diffuse DME is more prevalent in patients with an attached vitreous and usually has a poorer treatment prognosis treatment and visual outcome.

Clinical photograph showing hard exudates and mild diabetic macular edema.

Heidelberg Retina Tomograph (Heidelberg, Vista, Calif.) edema map (left) and reflectance map with corresponding graphical reading showing edema.

OCT printout with corresponding line scan showing corresponding area of thickening.

DME incidence

DME can be present at all levels of DR. It occurs in 20% of patients with type 1 diabetes after 10 years but is more common in patients with type 2 diabetes. Specifically, 25% of patients with type 2 diabetes who take insulin and about 14% of those who use oral hypoglycemic agents after 10 years have DME. Also, DME is three times more likely to occur in patients with poorly controlled concomitant hypertension.

The insidious onset of diabetic macular edema along with the adaptive response by the patient to gradual progression of retinal thickening makes the clinical diagnosis more challenging. Patients with clinically significant macular edema (CSME) may have normal Snellen acuity and color vision and may be free from Amsler grid abnormalities.

The ETDRS established guidelines for the treatment and management of DR and DME. The study showed that the risk for moderate vision loss (doubling of the visual angle) can be reduced by 50% with focal laser treatment in cases of CSME.

Associated risk factors for DME include worsening of glycemic control, duration of diabetes, hypertension and hypercholesterolemia. In the Wisconsin Epidemiologic Diabetic Retinopathy Study, diabetic patients with hypertension had a three times greater risk of developing DME. Additionally, a number of studies have noted that when the vitreous remains attached to the retina in the macular area there is a greater chance for developing DME. Posterior separation of the posterior hyaloid face of the vitreous seems to reduce the risk for DME, especially diffuse edema.

Diagnosing DME

	Hard exudates and punctate intraretinal hemorrhages in a patient with clinically significant macular edema.
	Red free photography in the same patient.

The gold standard for diagnosing DME is 35-mm stereoscopic fundus photography. However, recent advances in digital retinal imaging technology have improved our ability to determine the presence of retinal thickening.

Devices such as scanning laser ophthalmoscopes and optical coherence tomography with spectral domain technology are some of the newer technologies that enhance our ability to diagnose and ultimately treat DME. These devices have the capability of verifying diagnostic findings and for confirming suitability and eligibility for treatment of DME. While new technology improves our ability to diagnose DME, we still must rely on fundus fluorescein angiography to identify sites of focal or diffuse leakage characteristic of DME so that these areas can be treated with focal laser or modified grid focal argon green laser application.

More recent advances in technology can detect retinal thickening and other structural changes in the posterior pole, enhancing our ability to diagnose and ultimately treat impending, beginning or worsening DME. These technologies can verify diagnostic findings and determine suitability and eligibility for treatment. In spite of the advancement of technology in primary care practice, fundus fluorescein angiography remains the method to localize the sites of focal or diffuse leakage that might require treatment.

Some of the newer technologies include the Heidelberg Retinal Tomograph 3 (HRT 3, Heidelberg Engineering, Vista, Calif.) and the OCT Stratus (Carl Zeiss Meditec, Dublin, Calif.) The HRT 3 is a confocal laser scanning system that acquires a series of images at different focal planes and forms a three-dimensional rendering of the retina or optic nerve. The HRT 3 retina module (Macular Edema Module) obtains confocal tomographic images in the x, y and z plane, produces an intensity profile and determines the amount of light scatter. The results provide the examiner with a measurement indicating an index of retinal edema based on the amount of light scatter.

The OCT uses infrared light to obtain an image and measures retinal optical reflectivity to generate a map indicating retinal thickness. Media opacities can interfere with the imaging process with all three devices, however, thus limiting sensitivity and specificity in patients with cataract.

Biochemical mechanisms, novel therapies

Many mechanisms have been proposed for the microvascular and macrovascular complications associated with type 2 DM. Recently, it has been suggested that fluctuating blood glucose levels, such as those observed during postprandial glycemic excursions in people with IGT, may contribute significantly to oxidative stress.

Oxidative stress has been implicated as the collective pathogenic factor leading to insulin resistance, β-cell dysfunction and impaired glucose tolerance. Oxidative damage to enzymes and other important cellular components along with excess of glucose and fatty acid accumulation within muscle, adipose tissue and pancreatic cells leads to the generation of excess reactive oxygen species. Antioxidants, including genistein, a substance found in soy beans, may be effective as complementary treatment for type 2 DM.

VEGF is secreted by the retinal pigment epithelium and increases in concentration in a hypoxic retinal environment. It is likely expressed early in the course of hyperglycemia and, along with other mechanisms, induces a breakdown of the inner blood retinal barrier, ultimately leading to DR, DME and even neovascularization. The increased synthesis and expression of VEGF has been shown to accumulate in the nonvascular cells of the retina, thus giving credence to the theory that DR begins as a retinal neuronal disorder and only later becomes a retinal microangiopathic response.

Protein kinase C plays a role in downstream actions of VEGF and by binding with downstream receptors. Its presence within ocular tissue results in a mechanism that upregulates VEGF expression, thus contributing to the pathway leading to increased endothelial breakdown of the retinal vessels.

Oral protein kinase C ß-isoform inhibitors are being evaluated as a means of blocking the cascade of events that lead to DME and DR.

Additionally, there appears to be an inflammatory component to DME as a result of hyperleukosis. The increased leukocyte adherence to vessel walls alters retinal blood flow and increases the breakdown of the inner blood retinal barrier, thus contributing to DME.

Pigment epithelial derived factor (PEDF), a neovascular inhibitor, is produced in retinal neurons and in glial cells. PEDF and VEGF are reciprocal, and PEDF is secreted in other parts of the eye and elsewhere in the body. It is an important element in helping maintain the integrity of the retina’s neural structure (Mueller’s cells), and the concentration of PEDF decreases as VEGF increases. Studies are ongoing using nonreplicating adenovirus introduced into the eye to stimulate PEDF formation in ocular tissue.

While focal or modified focal grid laser treatment remains the mainstay of treatment for DME, a number of alternative or supplementary therapeutic approaches are being investigated for DR and DME. In fact, VEGF appears to be suppressed by extensive scatter (panretinal) laser photocoagulation. Several clinical studies, in progress or pending, are looking at alternate treatment modalities and routes of administration, including oral administration and intravitreal injection, as preventive or adjunctive therapy.

It is now thought that angiogenic factors play an early role in the pathogenesis of DR and diabetic macular edema. Because VEGF expression is enhanced by hypoxia, antiangiogenic agents are logical surrogates for treating DR and DME.

Clinical trials in various stages are employing intravitreal injection Kenalog (triamcinolone, Bristol-Meyers Squibb) and Posurdex (dexamethasone, Oculex/Allergan) to treat DME. Initially these agents are proving to be effective in reducing DME in recalcitrant or recurrent cases.

The mechanism of action in restoring the integrity of the inner blood retinal barrier likely relates to the role of corticosteroids in inhibiting prostaglandin activity, thus reducing the effect of the VEGF. VEGF inhibitors such as Macugen (pegaptanib sodium, OSI Eyetech/Pfizer), Lucentis (ranibizumab, Genentech/Novartis Ophthalmics) and the off-label Avastin (bevacizumab, Genentech) are some widely used yet poorly studied anti-VEGF treatments. Avastin, a larger molecular weight version of ranibizumab approved by the Food and Drug Administration for treating metastatic colorectal cancer and also administered by intravitreal injection, appears to have potential in treating DME. Investigative studies are either underway or in evolution.

Prophylactic vitrectomy has also been used to reduce thickening in the macula from diabetes because studies have shown that it is more likely for a patient to have DME when the posterior hyaloid face of the vitreous remains attached to the macula.

DR research network

The Diabetic Retinopathy Clinical Research Network (DRCR.net) is a National Eye Institute-funded collaborative network dedicated to facilitating multicenter clinical trials for DR, diabetic macular edema and related conditions. Established in 2002, the DRCR.net supports multicenter clinical research and epidemiologic outcomes initiatives focused on diabetes-induced retinal disorders.

The challenge for optometry

While retinal microangiopathy is of foremost concern to the optometrist, diabetes remains a complex disease with important lifelong consequences for the patient. As its prevalence reaches epidemic proportions, health care providers face formidable challenges.

Concomitant systemic disorders can exert undue influence on the development, progression and ultimate outcome of diabetic eye disease and other microvascular complications. Timely, coordinated care and optimal control of concurrent morbidities can significantly improve the prognosis for the patient with diabetes.

For more information:

• Anthony A. Cavallerano, OD, a Primary Care Optometry News Editorial Board member, is a staff optometrist, researcher and training center coordinator at VA Boston Health Care System Ocular Telehealth Program in Boston. He is also an attending optometrist with the VA Boston Health Care System. Dr. Cavallerano can be reached at Boston VA Health Care System, Jamaica Plain Campus 9B-61, 150 S. Huntington Ave., Jamaica Plain MA 02130; (857) 364-2281; e-mail: anthony.cavallerano@va.gov. Dr. Cavallerano has no direct financial interest in the products mentioned in this article, nor is he a paid consultant for any companies mentioned.

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