An Optometrist’s Guide to a Growing, Yet Treatable, Disease

W. Lloyd Clark, MD Paul Karpecki, OD

Sponsored by

061516_regeneron.indd 1 6/2/16 4:55 PM PREVALENCE OF : DME IN THE US An Optometrist’s Guide to a Growing, • In the United States, ap- proximately 21% of people Yet Treatable, Disease with diabetes, or 8 million individuals, have (DR).6 Only about 5.8 million of these are diagnosed.6,18,19 oth the prevalence and incidence of diabetes have • Of these 8 million peo- increased considerably over the past decade and show ple, about 2.3 million have no signs of slowing down. Make no mistake, diabetes is diabetic macular edema (DME), 1.5 million are now considered to be an epidemic in the United States. diagnosed and 750,000 BIt affects 9.3% of the US population (29.1 million people) and have clinically signifi cant 1 is the seventh leading cause of death. An additional 86 million macular edema (CSME)6,19 adults in the United States have prediabetes based on their fast- • Of those with CSME, only ing glucose or HbA1c levels and are at risk to develop diabetes.2 about 400,000 are receiv- It is projected that by 2050, as many as one in three to fi ve ing treatment for DME.8 adults will have diabetes.3

ABOUT THE AUTHORS

W. Lloyd Clark, MD, is an ophthalmologist and Paul Karpecki, OD, received his doctor of optome- managing member at Palmetto Retina Center, LLC, try degree from Indiana University and completed in Columbia, SC. He is also clinical as- a fellowship in medical cornea and re- sistant professor of at fractive surgery in Kansas City in affi li- University of South Carolina School of ation with the Pennsylvania College of Medicine. Optometry. He currently practices at Kentucky Eye Institute. Dr. Clark specializes in vitreoretinal diseases and surgery. His clinical inter- Dr. Karpecki was one of two optome- ests include pharmacologic management of retinal trists appointed to the Delphi International Society vascular disease, complex retinal detachment and at Wilmer Eye Institute at Johns Hopkins, which in- retinopathy of prematurity. In addition to main- cluded the top 25 dry eye experts in the world, and taining an active referral practice in medical and the National Eye Institute’s Dry Eye Committee, to surgical retina, he operates a broad-based clinical provide insights around the prevalence or incidence research program. Dr. Clark participates in nation- of dry eye in women. al and international multicenter trials sponsored by industry and the National Institutes of Health as A noted educator and author, he is the chief clinical well as investigator-sponsored trials. He has written editor of Review of Optometry. Dr. Karpecki is also investigator-initiated clinical trial protocols for Ge- past president of the Optometric Cornea, Cataract nentech-Roche and Regeneron Pharmaceuticals. and Refractive Society and serves on the board for He also sits on the Retinal Vein Occlusion Steering the charitable organization Optometry Giving Sight. Committee for Regeneron, the Protocol B Steering committee for NIH-sponsored Diabetic Retinopathy Clinical Research (DRCR) Network and the Scientif- ic Advisory Board for Santen Pharmaceuticals. Dr. Clark provides consulting services to all stakehold- ers in the fi eld of retinal diseases and therapy.

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061516_regeneron.indd 2 6/2/16 5:02 PM Americans are also getting diabetes at increasingly younger ages.1,2 One of the ma- jor drivers for this in- crease is obesity, which is a major risk factor for type 2 diabetes. Rates of obesity have increased from 20.1% in 2000 to 27.6% in 2012, and are a likely driver of the increase in diabetes rates.4 Patients must be made aware Whatever the cause, that diabetic macular edema can diabetes and its com- plications are an develop at any stage of diabetes enormous burden on and is often asymptomatic. the healthcare system. Patients with diabetes visit a doctor about 24 times each year, on average, to address structures of the eye and many aspects of the many complications related to this visual function.10 disease.5 Specifi c to ocular complications, Diabetic retinal disease, the most com- approximately 21% of patients with dia- mon microvascular complication of diabe- betes develop diabetic retinopathy (DR)6 tes, is a leading cause of vision loss among and, among those who do, 70% will have adults worldwide. It primarily manifests as diabetic macular edema (DME).7 Unfortu- diabetic retinopathy and/or diabetic macu- lar edema. It is essential that diabetic patients Patients with diabetes are receive screening for retinal disease so also at an increased risk of non-retinal ocular compli- that appropriate interventions can be cations, including:10 initiated before irreversible damage • Changes in visual func- occurs.10,11 tion, such as loss of visual acuity, refractive error changes, changes in color nately, by 2020 approximately 9.6 million vision, accommodative dysfunction and Americans will have diabetic retinopathy.8 visual fi eld changes For this reason, our responsibility as eye • Eye movement anomalies secondary to care providers to carefully monitor diabet- diabetic neuropathy ic and prediabetic patients is crucial. • Sluggish pupillary refl exes • Microaneurysms in the bulbar conjunc- OCULAR COMPLICATIONS tiva and an increased risk of conjunctival OF DIABETES bacterial infections Up to 45% of people with diabetes ex- • Tear fi lm abnormalities leading to an perience vision loss.9 Diabetes impacts all increased incidence of dry eye

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• Corneal abnormalities, such as slower may present with microaneurysms, intra- wound healing, reduced corneal sensitivity, retinal hemorrhage, vitreous hemorrhage, abrasions and contact lens–related micro- exudates, macular ischemia, neovascular- bial keratitis ization and tractional retinal detachment. • Iris abnormalities, such as depigmen- Seventy percent of patients with the most tation, neovascularization of the iris and severe form of diabetic retinopathy will neovascular glaucoma experience progression to diabetic macular • Cataracts, including reversible lenticular edema.7 opacities • Vitreous degeneration and posterior vit- UNDERSTANDING reous detachment (PVD), which may play BARRIERS TO CARE a role in PDR It is essential that diabetic patients • and nerve abnormalities, such receive screening for retinal disease so that as diabetic papillopathy and ischemic optic appropriate interventions can be initiat- neuropathy ed before irreversible damage occurs.10,11 However, nearly one in four patients with dia- betes age 40 years and older is not complying with the recommended yearly eye exam.13 There are several reasons why patients don’t receive annual eye exams. According to a 2014 study on barriers to eye care in diabetes patients, the Color can aid in most commonly cited documenting and evaluating more reasons for not getting exams are “no need” severe cases of DME while helping (39.7%) and cost or lack to track disease progression and of insurance (32.3%).13 treatment response. Other reasons are: not having an eye doctor, not being able to make an appointment with a • Primary open angle glaucoma doctor and not having transportation to an Diabetic retinopathy disease severity appointment. varies greatly, ranging from no disease and People ≥65 years of age were more likely no signs or symptoms, to nonproliferative to report “no need” as their main reason diabetic retinopathy (which can be mild, for being noncompliant, whereas those moderate or severe), to proliferative dia- 40 to 64 years of age and women overall betic retinopathy and possible severe vision were more likely to report “cost or lack of loss due to neovascularization.11 Macular insurance” as their main reason. edema may occur at any stage of DR.12 As Given that “no need” was the most diabetic retinopathy progresses, patients commonly cited reason for not seeking eye

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061516_regeneron.indd 4 6/2/16 4:51 PM Why Patients Don’t Receive Other Annual Eye Exams As reported by patients 21.5 diagnosed with diabetes who No eye No are not receiving annual eye doctor, no need* exams. transportation, 6.4 39.7 or could not get • Patients with visual appointment impairments are more likely to cite “cost or lack of insurance” 32.3 as a reason for not receiving an eye exam and less likely to report “no need” Cost/lack of insurance *Consisted of “have not thought Chou CF, et al. Diabetes Care. 2014;37:180-8. of it” and “no reason to go”

care, diabetes eye health education pro- diabetes has on vision can help reduce the grams or interventions that increase the numbers who believe there is no need for awareness of the need for eye care among an exam. people with diabetes may be effective Furthermore, targeting simple interven- strategies toward helping to protect against tions (such as reminders) to patients with a vision loss. lower income, those 40 to 64 years old, pa- tients without health insurance and those HOW TO GET PATIENTS who have been diagnosed with diabetes INTO THE OFFICE for a longer amount of time can encourage Education is vital in the effort to con- patients to seek annual dilated eye exams. nect with the 23.5% of patients who are noncompliant with their eye exams and get WHEN TO REFER1,2 them into the offi ce.13 To begin, we need to An annual dilated eye examination and increase awareness be- tween healthcare profes- sionals and adults with IMMEDIATE High-risk REFERRALS: diabetes 65 years and DME (within PDR (within • Traction 2-4 weeks) retinal older of the importance 24-48 hours) detachment of annual eye exams. • Vitreous hemorrhage Patients must be made aware that diabetic mac- ular edema can develop at any stage of diabetes Severe or When to refer PDR and is often asymp- very severe to a retina (within 2 tomatic. Older adults NPDR (2-4 weeks) weeks) specialist might not be aware of their vision impairment because symptoms prog- ress slowly or they may Moderate CSME consider vision loss to be NPDR (2-4 (within 2 a normal part of aging. weeks) weeks) Increased education regarding the effect

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fundus photographs, if indicated, are cases of DME while helping to track dis- generally suffi cient for the patient with ease progression and treatment response.11 mild nonproliferative diabetic retinopathy Fluorescein angiography also may be (NPDR), as long as there is neither macu- used to evaluate unexplained decreases in lar edema nor a coincident medical condi- visual acuity.17 This test is considered most tion, such as hypertension, renal disease or helpful in determining site of leakage in pregnancy.14 those with DME, as well as characterizing Any patient with DME or with suspected the severity of DR, assessing the extent of DME should be referred to a retina special- capillary nonperfusion and confi rming neo- ist within two to four weeks for evalua- vascularization.16,17 tion. The patient with high-risk prolifera- tive diabetic retinopathy (PDR) should be DIABETIC MACULAR referred to a retina specialist more quickly, EDEMA TREATMENT usually within 24 to 48 hours. If a patient Of the 2.3 million patients with diabetic with high-risk proliferative diabetic reti- macular edema, only about half a million nopathy has a traction retinal detachment are treated for it.6,18,19 However, this is not or vitreous hemorrhage, they should be due to lack of therapeutic options. Al- referred immediately. though there is no cure for diabetic macu- Those with clinically signifi cant macular lar edema, treatment options are available. edema should be referred quickly as well, A variety of therapies have been studied within two weeks. Patients whose prolifer- over the years, and the treatment landscape ative diabetic retinopathy is less than high for diabetic macular edema has evolved. risk or who have signs of moderate, severe Current therapies include laser treatments, or very severe nonproliferative diabetic steroids and vascular endothelial growth retinopathy should also be referred for factor (VEGF) inhibitors. Anti-VEGF consultation.14,15 therapies are now widely used as frontline therapy for many patients with diabetic IDENTIFYING PROGRESSION Recognizing the progression of DME Prevalence of DME in the US involves several tests in addition to the eye Approximately 8 million (21%) of people exam. For example, optical coherence to- with diabetes have DR1 mography (OCT) creates high-resolution, • 5.8 million are diagnosed1-3 cross-sectional images of body structures • 2.3 million have DME3 by illuminating them with infrared light and measuring the refl ected light.16 It is 8.0MM1 used in DME patients to detect and assess 5.8MM1-3 thickening of the retina due to edema.11 However, it is important to note that OCT 2.3MM3 1.5MM3 alone can miss areas of macular edema. If ≈400K4 an OCT is taken only through the central DR DR DME DME DME Prevalence Diagnosed Prevalence Diagnosed Treated macula, some increase in central retinal thickness may be missed. For this reason, it 1. NHANES 2005-2008, projected to 2012 US population. 2. Centers for Disease Control and Prevention. www.cdc.gov. Accessed is important to conduct imaging in addi- June 9, 2014. Saaddine JB, et al. Arch Ophthalmol. 2008;126(12):1740-7. 3. BioTrends Research Group. TreatmentTrends®: Diabetic Retinopathy/ tion to the OCT. Diabetic Macular Edema (US) 2013. 4. Proprietary Quantitative Market Research (n=103 retina specialists, Color fundus photography may help in n=23,994 DME eyes with central involvement); fi elded November 2013. documenting and evaluating more severe

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0061516_regeneron.indd61516_regeneron.indd 6 66/2/16/2/16 4:494:49 PMPM macular edema.20-22 Vascular endothe- lial growth factor-A (VEGF-A) plays an important role in the pathophysiology of DME.23 Diabetic reti- nopathy causes micro- vascular damage in the retina, which reduces perfusion to the dam- aged areas and results in retinal hypoxia.23 Fluorescein angiography may This hypoxia causes be used to evaluate unexplained increased expression of VEGF-A, which in turn decreases in a patient’s visual acuity. increases permeability and vascular leakage

thereby producing Past, Present, and Future Therapies. Ophthalmology Monographs 14. DME.23 2nd ed. New York, NY: Oxford University Press; 2009. 8. Data on fi le, Regeneron. Proprietary Quantitative Market Research (n=103 retina specialists, n=23,994 DME eyes with central involve- CONCLUSION ment); fi elded November 2013. 9. National Institutes of Health. NIH Senior Health Web site. Diabetic The diabetes epidemic is taking a sig- Retinopathy: Causes and Risk Factors. http://nihseniorhealth.gov/ diabeticretinopathy/causesandriskfactors/01.html. Accessed February nifi cant toll on the health of our nation’s 6, 2015. citizens and resources. Effective screening, 10. AOA Evidence-Based Optometry Guideline Development Group. Eye Care of the Patient with Diabetes Mellitus: Evidence-Based Clinical Prac- education and frequent exams are essential tice Guideline. St. Louis, MO: American Optometric Association; 2014. to prevent the likelihood of vision loss. 11. American Academy of Ophthalmology Retina/Vitreous Panel. Preferred Practice Pattern® Guidelines. Diabetic Retinopathy. San Fran- The optometrist plays a central role in this cisco, CA: American Academy of Ophthalmology; 2008 (4th printing 2012). www.aao.org/ppp. Accessed November 26, 2013. regard. ODs must be meticulous in their 12. Brownlee M, Aiello LP, Cooper ME, et al. Complications of diabetes exams, thorough in their explanations mellitus. In: Melmed S, Polonsky KS, Larsen PR, Kronenberg HM, eds. Williams Textbook of Endocrinology. 12th ed. Philadelphia, PA: Elsevier clear with respect to explaining the ram- Saunders; 2011;1462-1551. ifi cations of missed visits and vigilant in 13. Chou CF, Sherrod CE, Zhang X, et al. Barriers to eye care among people aged 40 years and older with diagnosed diabetes, 2006-2010. their study on the literature with regard to Diabetes Care. 2014;37:180-8. ■ 14. American Optometric Association. Care of the Patient with Dia- available treatment options. betes Mellitus. https://www.aoa.org/documents/CPG-3.pdf. Accessed January 21, 2015. 1. Centers for Disease Control and Prevention. National diabetes sta- 15. Ferrucci S. Diabetic Retinopathy. AAOPT workshops. Academy tistics report, 2014. Atlanta, GA: US Department of Health and Human 2014, Denver. Services, Centers for Disease Control and Prevention, 2014. www.cdc. 16. Prall FR, Olson JL, Barnett CJ, et al. Fluorescein angiography, gov/diabetes/pubs/statsreport14/national-diabetes-report-web.pdf. indocyanine green angiography, and optical coherence tomography. In: Accessed June 30, 2014. Yanoff M, Duker JS, eds. Ophthalmology. 1991;98(suppl):823-33. 2. Centers for Disease Control and Prevention. Crude and age-adjusted 17. Rosenblatt BJ, Benson WE. Diabetic retinopathy. In: Yanoff M, Duker incidence of diagnosed diabetes per 1,000 population aged 18–79 JS, eds. Ophthalmology. 3rd ed. China: Mosby Elsevier; 2009:613-21. years, United States, 1980–2011. CDC Web site. http://www.cdc.gov/ 18. Saaddine JB, Honeycutt AA, Narayan KM, et al. Arch Ophthalmol diabetes/statistics/incidence/fi g2.htm. Accessed February 28, 2014. 2008;126(12):1740-7. 3. Boyle JP, Thompson TJ, Gregg EW, et al. Popul Health Metr. 2010 19. BioTrends Research Group. Treatment Trends: Diabetic Retinopa- Oct 22;8:29. thy/Diabetic Macular Edema (US) 2013. 4. Centers for Disease Control and Prevention. Prevalence and trends 20. Elman MJ, Ayala A, Bressler NM, et al. Diabetic Retinoathy Clinical data overweight and obesity (BMI)—2010. CDC Web site. http://apps. Research Network. Ophthalmology. 2015;122(2):375-81. nccd.cdc.gov/brfss/list.asp?cat=OB&yr=2000&qkey=4409&state=All. 21. Korobelnik JF, Do DV, Schmidt-Erfurth U, et al. Ophthalmology. Accessed February 28, 2014 2014;121(11):2247-54. 5. Data on File. Regeneron Pharmaceuticals, Inc. Tarrytown, NY. 22. Nguyen QD, Brown DM, Marcus DM, et al. Ophthalmology 6. Centers for Disease Control and Prevention. National Health and 2012;119(4):789-801. Nutrition Examination Survey (NHANES). 2005-2008, projected to 23. Boyer DS, Hopkins JJ, Sorof J, et al. Anti-vascular endothelial 2012 US population. growth factor therapy for diabetic macular edema. Ther Adv Endocri- 7. Scott IU, Flynn HW, Smiddy WE, eds. Diabetes and Ocular Disease: nol Metab. 2013;4(6):151-69.

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