This compendium is intended as a guide to diabetes-related eye disease for primary care providers (PCPs), who treat the vast majority of people with diabetes in the United States. Its goal is to provide the information PCPs need to understand the eye complications of diabetes and effectively counsel patients about them. The chapters included offer discussions of 1) diabetes-related risk factors for vision impairment; 2) cataracts and cataract surgery in people with diabetes; 3) diabetes-related retinopathy (DR), including its pathogenesis, classification, diagnosis, and treatment; and 4) the emotional aspects of diabetes-induced vision impairment. The underlying premise is that PCPs and ophthalmologists share common goals in collaborating to care for people with diabetes.

Diabetes affects the eyes as part of its systemic effects on all organs, ranging from the kidneys, peripheral nerves, and retinas, to the heart, adipose tissue, liver, and muscle, and even to skin and the brain. Diabetes is a leading cause of vision loss and blindness in working-age adults, with 245 million people affected worldwide (1). Fortunately, rates of vision impairment in the United States and Europe have declined dramatically over the past three decades due to improved systematic management of diabetes, the development of standardized DR screening programs in several European counties (2,3), and the advent of anti-vascular endothelial growth factor (VEGF) therapy (4). However, worldwide, approximately 35% of people with diabetes develop some form of DR, although not all patients lose vision, just as not all patients with nephropathy will require dialysis for end-stage renal disease. Vision-threatening DR, that which requires treatment, develops in about 10% of people with diabetes (1). The expanding population of people with diabetes worldwide thus yields millions of people with DR. The burdens of diabetes and DR are enormous, with total costs of $327 billion—that is, one in seven health care dollars attributable to diabetes—in the United States (5). Clearly, the emphasis must increasingly be to prevent or minimize the chronic complications of diabetes. DR and other complications are eminently preventable, but the tools and medications remain imperfect, and the resources required to achieve a life free of complications are daunting.

The primary ocular manifestations of diabetes are cataracts and DR. Cataracts are twice as common in people with diabetes than in those without diabetes (6) and are a common cause for the need for intraocular surgery. Fortunately, intensive metabolic control reduces the risks of cataract and intraocular surgery (6), at least for people with type 1 diabetes. Cataract surgery is one of the most common operations performed in the United States, and it has become much easier and safer and carries better outcomes now than 30 years ago. Still, cataracts remain a major cause of morbidity in people with diabetes.

DR is now understood to be a neurovascular degeneration or sensory neuropathy akin to other peripheral sensory neuropathies (4), and impairment of the invisible retinal neurons is the ultimate cause of vision impairment. Nonetheless, the primary clinical manifestations of DR are the visible vascular features of microaneurysms, hemorrhages, “cotton wool spots” (small yellowish-white deposits in the retina), and, in a minority of patients, eventual neovascularization (i.e., the formation of new blood vessels).

The ocular manifestations of diabetes develop in parallel with renal and neuropathic complications; they can present as manifestations of diabetes or of glucose intolerance (7), or they can develop in the late stages of the disease (8). The presence of DR, and particularly advanced DR, is associated with a greater risk of other systemic manifestations of diabetes, including stroke, heart attack, and renal insufficiency (9,10). Likewise, advancing renal disease, in particular, is likely to accelerate DR due to hypertension, anemia, and inflammation (11). Thus, the care of patients with DR is best managed as part of a coordinated systematic effort involving PCPs and ophthalmologists.

This compendium focuses on the vision-threatening aspects of diabetes. However, diabetes also affects the motor component of the visual system via cranial nerve palsies. The trigeminal nerve provides sensation to the face and cornea, and corneal sensory neuropathy is a common feature of long-standing diabetes (12,13). This feature is revealed by shortened corneal nerve fibers and reduced fiber density, but is usually asymptomatic. However, in severe cases, corneal neuropathy can increase the susceptibility to corneal abrasions, recurrent epithelial erosions, and infections.

Ocular motility is mediated primarily by the third and sixth cranial nerves, and ischemic insults to these nerves can present with double vision (third and sixth) or inability to close the eyelids (seventh). None of these palsies causes blurred vision. Third cranial nerve palsies associated with diabetes typically cause ptosis and paralysis of gaze toward the nose and inferiorly and ptosis of the upper lid, but do not cause pupil dilation. The finding of a dilated pupil strongly suggests intracranial compression of the oculomotor nerve and warrants prompt neuroimaging to rule out an aneurysm of the posterior communicating artery or a tumor (14). By contrast, a unilateral sixth-nerve palsy causes horizontal diplopia and a lateral out-turning of the affected eye. Seventh-nerve palsies from diabetes cause weakness of the entire half of the facial muscles without double vision. Diabetes-related third-, sixth-, and seventh-nerve palsies usually resolve spontaneously in 6–12 weeks.

Diabetes generally does not increase the risk of open-angle glaucoma, but neovascular glaucoma can develop in people with proliferative DR (PDR). This condition manifests with pain, tearing, and redness, with elevated intraocular pressure, and warrants urgent treatment.

Topics covered in this compendium were selected specifically to meet the information needs of PCPs. The first chapter was written by Dr. Jennifer A. Wyckoff, an endocrinologist, and Dr. Anjali R. Shah, an ophthalmologist and retina specialist. The chapter reflects their ongoing collaborative quality assurance/quality improvement work that recently identified hypertension as a previously unrecognized risk factor for the need to receive intravitreal anti-VEGF injections for DR (15). This finding arose from the ability to gather and analyze data from the electronic medical record (EMR) system at the University of Michigan to seek risk factors for DR progression that are not routinely monitored in ophthalmology-based clinical trials. Moreover, their work epitomizes the systemic nature of DR and the crucial collaboration between PCPs and ophthalmologists. That is, PCPs and other specialists must treat the hyperglycemia, dyslipidemia, hypertension, renal insufficiency, and anemia of chronic diabetes, and data related to these parameters should be readily available for ophthalmologists to interpret the status of their patients’ eye disease more effectively than with A1C data alone. Ophthalmologists, in turn, should communicate their findings, treatment plans, and information about prognosis to PCPs so they can act on their patients’ most pressing problems. Despite their challenges, EMRs can facilitate these communications.

Key points from this first chapter include:

  • The degree of hyperglycemia is important in the long-term risk of DR and other complications; reducing A1C by one percentage point can substantially reduce the risk of DR.

  • The degree of control of hyperglycemia and hypertension are more important than the specific agents used to achieve that control. Thus, treatment plans can be optimized for each patient.

  • Lifestyle interventions, notably diet and exercise, reduce the risk of complications and all-cause mortality in people with type 2 diabetes.

Our second chapter focuses on the complication of cataracts and their treatment. Dr. Jill E. Bixler, an experienced cataract surgeon, describes the transition from a clear crystalline lens to a cloudy cataract. Cataracts occur in various forms, with the posterior subcapsular and “snowflake” varieties being closely related to diabetes. Many factors are considered when determining the timing and type of surgery and the refractive goals for each patient.

Key points from this chapter include:

  • Intensive metabolic control reduces the risk of cataract formation and the need for cataract surgery.

  • Cataract surgery involves removal of the cloudy lens and replacement with a clear acrylic intraocular lens implant via two small incisions.

  • People with diabetes have very high success rates with cataract surgery despite a slightly higher risk of intraocular infection (endophthalmitis) compared to people without diabetes.

The third chapter provides a detailed discussion of DR—the most serious ocular complication of diabetes. Author Dr. Charles C. Wykoff is an expert in the care of people with DR and has led multiple clinical trials of new pharmacologic agents for its treatment. He clearly describes the processes through which DR develops and evolves, and when and how diagnostic and treatment strategies are formulated.

Key points from his chapter include:

  • Multiple retinal imaging tests are integral to the care of people with DR.

  • Intensive control of diabetes and related risk factors is the core of systemic therapy to optimize outcomes in people with DR.

  • Diabetes-related macular edema (DME) is the most common cause of reduced vision in people with DR and is usually treated with intravitreal injections of VEGF-blocking agents and/or corticosteroids, although laser treatment is useful in specific cases.

  • PDR can be successfully treated with either laser surgery or anti-VEGF agents.

  • Anti-VEGF agents may reduce the progression of moderate to severe nonproliferative DR (NPDR). Panretinal photocoagulation remains a common and important treatment for severe NPDR and PDR. In contrast to the accepted approaches to DME and PDR, standard clinical practices are still emerging for patients with NPDR.

Our final chapter was co-written by Dr. Blake A. Cooper and Dr. Ravi S.J. Singh, vitreo-retinal surgeons whose practice includes a large number of patients with DR. Their discussion of emotional support for people with DR is based on their insights into treating the whole person with diabetes. They emphasize a “3D view” of the distress, depression, and diabetes that often coexist in patients with diabetes and can lead to a sense of despair when an additional diagnosis of DR, often accompanied by neuropathies and/or nephropathy, is made.

Key points from Drs. Cooper and Singh include:

  • Self-care is a central feature of diabetes, in contrast to cancer or other serious diseases.

  • The language physicians use in communicating with people with diabetes is crucial, and empowering language should be employed.

  • Ophthalmologists can assure the vast majority of their patients that they will not become blind.

  • Physicians must help patients set realistic goals for the outcomes of ocular and systemic treatment of diabetes.

The opinions expressed are those of the authors and do not necessarily reflect those of Genentech or the American Diabetes Association. The content was developed by the authors and does not represent the policy or position of the American Diabetes Association, any of its boards or committees, or any of its journals or their editors or editorial boards.

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Dualities of Interest

T.W.G. has received research support from Zebra Biologics and consulting fees from Novo Nordisk.

C.C.W. has received research support from Adverum, Allergan, Apellis, Clearside, Genentech, Roche, Neurotech, Novartis, Opthea, Regeneron, Regenxbio, Samsung, and Santen; is a consultant for Adverum, Alimera Sciences, Allegro, Allergan, Apellis, Bayer, Clearside, EyePoint, Genentech, Kodiak, Novartis, Regeneron, Regenxbio, and Roche; and is a speaker for Regeneron.

B.A.C. has been a speaker for Novo Nordisk and served on an advisory board for Regeneron.

No other potential conflicts of interest relevant to this compendium were reported.

Acknowledgments

Editorial and project management services were provided by Debbie Kendall of Kendall Editorial in Richmond, VA.

Author Contributions

All authors researched and wrote their respective sections. Lead author T.W.G. reviewed all content and is the guarantor of this work.

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