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Home , Diabetic retinopathy, Retinopathy

412 Care Volume 40, March 2017

Diabetic : A Position Sharon D. Solomon,1 ,2 Elia J. Duh,1 Lucia Sobrin,3 Jennifer K. Sun,4 Statement by the American Brian L. VanderBeek,5 Charles C. Wykoff,6 and Thomas W. Gardner7 Diabetes Association

Diabetes Care 2017;40:412–418 | DOI: 10.2337/dc16-2641

Diabetic retinopathy diagnostic assessment and treatment options have improved dramatically since the 2002 American Diabetes Association Position Statement (1). These improvements include the widespread adoption of optical coherence tomog- raphy to assess retinal thickness and intraretinal pathology and wide-field POSITION STATEMENT photography to reveal clinically silent microvascular lesions. Treatment of diabetic is now achieved by intravitreous injection of anti–vascular endo- thelial growth factor agents, and the same drugs are now used for proliferative . Improvements in medications and devices for the systemic therapy of diabetes have also improved the ability of patients to optimize their metabolic control. This Position Statement incorporates these recent developments for the use of physicians and patients. 1Wilmer Eye Institute, Johns Hopkins Medicine, Diabetic retinopathy is a highly specific neurovascular of both type 1 and Baltimore, MD 2National Eye Institute, National Institutes of , the prevalence of which strongly correlates to both the duration of Health, Bethesda, MD diabetes and level of glycemic control. A pooled meta-analysis involving 35 studies con- 3Department of , Massachusetts ducted worldwide from 1980 to 2008 estimated global prevalence of any diabetic ret- Eye and Ear Infirmary, Boston, MA inopathy and proliferative diabetic retinopathy (PDR) among patients to be 35.4% and 4Beetham Eye Institute, Joslin Diabetes Center, Boston, MA 7.5%, respectively (2). Diabetic retinopathy is the most frequent cause of new cases of 5 – Department of Ophthalmology, University of blindness among adults aged 20 74 years in developed countries. , , Pennsylvania, Philadelphia, PA and other disorders of the eye occur earlier and more frequently in people with diabetes. 6Retina Consultants of Houston, Houston, TX In addition to diabetes duration, factors that increase the risk of or are associated 7Department of Ophthalmology and Visual Sci- with retinopathy include chronic (3,4), nephropathy (5), ences, Kellogg Eye Center, University of Michi- (6), and dyslipidemia (7). Intensive with the goal of achieving gan, Ann Arbor, MI near-normoglycemia has been shown in large prospective randomized studies to Corresponding author: Thomas W. Gardner, [email protected]. prevent and/or delay the onset and progression of diabetic retinopathy (8,9). Lowering pressure has been shown to decrease retinopathy progression in This position statement was reviewed and ap- proved by the American Diabetes Association people with type 2 diabetes, although tight targets (systolic Professional Practice Committee in October ,120 mmHg) do not impart additional benefitovertargetsof,140 mmHg (9,10). In 2016 and ratified by the American Diabetes As- patients with dyslipidemia, retinopathy progression may be slowed by the addition of sociation Board of Directors in December 2016. fenofibrate, particularly with very mild nonproliferative diabetic retinopathy (NPDR) at For further information on the ADA evidence- baseline (7). Several case series and a controlled prospective study suggest that preg- grading system and the levels of evidence, please nancy in patients with may aggravate retinopathy and threaten vision, see Table 1 in the American Diabetes Associa- tion’s Introduction section of the Standards of especially when glycemic control is poor at the time of conception (11,12). Medical Care in Diabetesd2017. Diabetes Care 2017;40(Suppl. 1):S2. NATURAL HISTORY © 2017 by the American Diabetes Association. Readers may use this article as long as the work Recommendations is properly cited, the use is educational and not c Optimize glycemic control to reduce the risk or slow the progression of for profit, and the work is not altered. More infor- diabetic retinopathy. A mation is available at http://www.diabetesjournals .org/content/license. care.diabetesjournals.org Solomon and Associates 413

producing severe and often irreversible vi- studies performed in the modern era of c Optimize blood pressure and se- sion loss. Third, the new blood vessels may expanded options for , , and rum lipid control to reduce the bleed, adding the further complication of blood pressure control. risk or slow the progression of di- preretinal or . These The WESDR found a relationship be- abetic retinopathy. A clinically evident vascular changes are ac- tween onset of retinopathy and du- companied by damage to retinal ration of diabetes. It established that In general, retinopathy advances from (15), the final common pathway for vision progression of retinopathy was a function mild nonproliferative abnormalities, char- loss. of baseline retinopathy. More severe base- acterized by increased numbers of micro- Several epidemiological studies have line retinopathy led to a greater frequency that may wax and wane. With described the progression rates for di- of progression to vision-threatening re- increasing severity, there is increased vas- abetic retinopathy. The cohort with the tinopathy. Among patients with type 2 cular permeability and occlusion and pro- longest follow-up is the Wisconsin Epide- diabetes whose baseline photographs gression from moderate and severe NPDR miologic Study of Diabetic Retinopathy showed no retinopathy, there was 54% to PDR, characterized by the growth of (WESDR), which reported the 25-year less progression to PDR over 10 years com- new blood vessels on the and pos- progression of diabetic retinopathy in pared with those with severe NPDR at terior surface of the vitreous (see Table 1 patients with type 1 diabetes (16). How- baseline (17). The WESDR epidemiologi- for definitions of diabetic retinopathy ever, the WESDR started recruitment in cal data were limited primarily to white stages). and puberty can accel- 1979 when options for glycemic, blood Northern European extraction popula- erate these changes (12,13). sur- pressure, and lipid control were mark- tions and may not be applicable to Afri- gery has not been definitely demonstrated edly limited compared with the options can American, Hispanic American, or by recent studies to accelerate the pro- available today. The risk factors identi- Asian American populations or to others gression of diabetic retinopathy, espe- fied in WESDRdlonger duration of dia- with a high prevalence of diabetes and cially in the more recent era of treating betes, greater hyperglycemia, increased retinopathy. both diabetic macular edema (DME) blood pressure, and dyslipidemiad After duration of diabetes, hypergly- and PDR with the use of anti–vascular remain relevant while the progression cemia has been the most consistently endothelial growth factor (anti-VEGF) rates in more recent studies may differ associated risk factor for retinopathy. agents (14). markedly. For example, the WESDR pro- A large and consistent set of observa- Vision loss due to diabetic retinopathy gression data predicted a progression tional studies and clinical trials document results from several mechanisms. First, rate near 40% over 4 years for the Ac- the association of poor glucose control central vision may be impaired by macular tion to Control Cardiovascular Risk in Di- and retinopathy. The Diabetes Control edema as the result of increased vascular abetes (ACCORD) trial, but the actual and Complications Trial (DCCT), a ran- permeability and/or capillary nonperfu- progression rate in people with type 2 domized controlled clinical trial of inten- sion. Second, the new blood vessels of PDR diabetes at the study’s conclusion was sive glycemic control versus conventional and contraction of the accompanying fi- only 10%. Table 2 shows the odds ratios glycemic control in people with type 1 brous tissue can distort the retina and associated with the most consistently as- diabetes, demonstrated that intensive lead to tractional , sociated retinopathy risk factors in therapy reduced the development or progression of diabetic retinopathy by 34–76% (51). In addition, the DCCT demonstrated a definitive relationship Table 1—Diabetic retinopathy stages* between hyperglycemia and diabetic Diabetic retinopathy microvascular complications, including stage Description retinopathy (18). Early treatment with Mild NPDR Small areas of balloon-like swelling in the retina’s tiny blood vessels, called intensive therapy was most effective. In microaneurysms, occur at this earliest stage of the disease. These addition, intensive therapy had a sub- fl microaneurysms may leak uid into the retina. stantial beneficial effect over the entire Moderate NPDR As the disease progresses, blood vessels that nourish the retina may swell range of retinopathy. A 10% reduction in and distort. They may also lose their ability to transport blood. Both HbA , for example from 10 to 9% or conditions cause characteristic changes to the appearance of the retina 1c and may contribute to DME. from 8 to 7.2%, reduces the risk of reti- Severe NPDR Many more blood vessels are blocked, depriving blood supply to areas of nopathy progression by 43% (52). the retina. These areas secrete growth factors that signal the retina to The UK Prospective Diabetes Study grow new blood vessels. (UKPDS) of patients newly diagnosed PDR At this advanced stage, growth factors secreted by the retina trigger the with type 2 diabetes conclusively dem- proliferation of new blood vessels, which grow along the inside surface onstrated that improved blood glucose of theretina and intothe vitreous gel, the fluid thatfillstheeye.Thenew control in those patients reduced the blood vessels are fragile, which makes them more likely to leak and risk of developing retinopathy and ne- bleed. Accompanying scar tissue can contract and cause retinal phropathy and possibly reduced the detachmentdthe pulling away of the retina from underlying tissue, like wallpaper peeling away from a wall. Retinal detachment can lead risk for neuropathy (8). The overall mi- to permanent vision loss. crovascular complication rate was de- creased by 25% in patients receiving *Adapted from https://nei.nih.gov/health/diabetic/retinopathy. intensive therapy versus conventional 414 Position Statement Diabetes Care Volume 40, March 2017

fi Table 2—Recent estimates of the association between major risk factors and feno brate was not evident after the diabetic retinopathy drug was stopped in the clinical trial of Risk factor Reference Strength of association, odds ratio (95% CI) ACCORD. This suggests that the treat- ment with fenofibrate therapy may in- Duration of diabetes Xu et al. (48) 1.16 (1.10–1.22) per year increase deed be real. Kajiwara et al. (49) 1.13 (1.09–1.17) per year increase The results of these two large ran- HbA Xu et al. (48) 1.73 (1.35–2.21) per 1% increase 1c domized trials, ACCORD Eye Study and Kajiwara et al. (49) 1.21 (1.08–1.36) per 1% increase FIELD, suggest that fenofibrate may be a Jin et al. (50) 1.12 (1.01–1.24) per 1% increase potential therapy for people with dia- Blood pressure Kajiwara et al. (49) 1.02 (1.01–1.03) per mmHg increase in systolic blood pressure betic retinopathy. These results were Jin et al. (50) 1.80 (1.14–2.86) if systolic blood not subgroup analyses, and these bene- pressure .140 mmHg and/or ficial effects were supported by two diastolic blood pressure .90 mmHg large randomized controlled clinical tri- als. Because of the lack of beneficial ef- fects on cardiovascular disease, medical physicians have been reluctant to pre- therapy. Epidemiological analysis of the UKPDS showed a 37% reduction in mi- scribe fenofibrate for people with dia- UKPDS data showed a continuous rela- crovascular abnormalities, including di- betic retinopathy. There are sufficient tionship between the risk of microvas- abetic retinopathy and specifically DME, data to suggest developing collaboration cular complications and glycemia, such with lowering of systolic blood pressure between the ophthalmologists (eye care that every percentage point decrease in from a mean of 154 mmHg to 144 mmHg providers) and the medical physician to HbA1c (e.g., 9% to 8%) was associated (20). However, the more recent ACCORD consider this treatment for people af- with a 35% reduction in the risk of mi- Eye Study did not show either a harmful fected with diabetic retinopathy. crovascular complications. or a beneficial effect when comparing sys- More recently, the ACCORD trial of tolic pressure of 120 mmHg vs. 140 mmHg medical therapies demonstrated that in- in a similar cohort of patients (9). Recommendations tensive glycemic control reduced the Several observational studies have sug- c Adults with type 1 diabetes should risk of progression of diabetic retinopa- gested that dyslipidemia may play a role have an initial dilated and compre- thy in people with type 2 diabetes of in the progression of diabetic retinopa- hensive by an oph- 10 years duration (9). This study in- thy. Dyslipidemia is associated with reti- thalmologist or optometrist within cluded 2,856 ACCORD participants who nal hard exudate and visual loss. Two 5 years after the onset of diabetes. B were enrolled into the ACCORD Eye trials of fenofibrate have been conducted c Patients with type 2 diabetes should Study and followed for 4 years. to reduce the levels of serum triglycerides have an initial dilated and compre- The results of the DCCT, UKPDS, and in an effort to reduce cardiovascular risk hensive eye examination by an oph- ACCORD Eye Study showed that while (9,21). Although fenofibrate does not thalmologist or optometrist at the intensive therapy does not prevent ret- have an effect on cardiovascular risk, time of the diabetes diagnosis. B inopathy completely, it reduces the risk both studies showed an effect on the pro- c If there is no evidence of retinopa- of the development and progression of gression of diabetic retinopathy. The thy for one or more annual eye ex- diabetic retinopathy. This can be trans- Fenofibrate Intervention and Event ams, then exams every 2 years may lated clinically to a higher likelihood of Lowering in Diabetes (FIELD) study be considered. If any level of dia- preserving sight and to a reduced need demonstrated the beneficial effects of betic retinopathy is present, subse- for treatment. Furthermore, all three fenofibrate (200 mg daily) versus placebo quent dilated retinal examinations studies demonstrated that years after in reducing the need for laser photocoag- for patients with type 1 or type 2 the initial clinical trial ended, the treat- ulation (hazard ratio 0.69, 95% CI 0.56– diabetes should be repeated at ment effect of intensive glycemic control 0.84, P = 0.00002) (21). A substudy of the least annually by an ophthalmolo- persisted, despite the fact that both treat- FIELD participants with fundus photo- gist or optometrist. If retinopathy ment groups had similar levels of HbA .In graphs showed the beneficial effect on 1c is progressing or sight-threatening, fact, 25 years after the cessation of the the Early Treatment Diabetic Retinopathy then examinations will be required DCCT, ocular surgery rates were reduced Study (ETDRS) scale, especially in those more frequently. B in those who had been assigned to inten- with retinopathy at baseline and also on c Womenwithpreexistingtype1or sive glycemic control (19). In the DCCT, at the development of macular edema (haz- type 2 diabetes who are planning varying intervals, the beneficial effects of ard ratio 0.66, 95% CI 0.47–0.94, P = 0.02). pregnancy or who have become intensive glycemic control persisted but The ACCORD Study also compared feno- pregnant should be counseled on declined over time. This persistent ben- fibrate 160 mg daily with simvastatin the risk of development and/or pro- eficial effect beyond the clinical trial was versus placebo with simvastatin and gression of diabetic retinopathy. B true for people with type 1 and type 2 found that the risk of progression of c Eye examinations should occur be- diabetes. diabetic retinopathy was reduced by fore pregnancy or in the first trimes- Blood pressure control has also been one-third. The effect was particularly ter in patients with preexisting studied in several observational and demonstrated in those with preexisting type 1 or type 2 diabetes, and then clinical trials, including the UKPDS. The diabetic retinopathy. The effect of care.diabetesjournals.org Solomon and Associates 415

minimal to no retinopathy. Exams every 78 diopter), indirect , these patients should be monitored 2 years may be cost-effective after one and testing as appropriate that may in- every trimester and for 1 year post- or more normal eye exams and, in a pop- clude optical coherence tomography partum as indicated by the degree of ulation with well-controlled type 2 dia- and fluorescein angiography. retinopathy. B betes, there was essentially no risk of Retinal photography, with remote c While retinal photography may development of significant retinopathy reading by experts, has great potential serve as a screening tool for retinop- with a 3-year interval after a normal exam- to provide screening services in areas athy, it is not a substitute for a com- ination (26). Examinations will be required where qualified eye care professionals prehensive eye exam, which should more frequently by the ophthalmologist if are not readily available (31). High-quality be performed at least initially and retinopathy is progressing. fundus photographs can detect most at intervals thereafter as recom- Pregnancy can be associated with rapid clinically significant diabetic retinopathy. mended by an eye care profes- progression of diabetic retinopathy in the Interpretation of the images should be sional. E setting of type 1 and type 2 diabetes (27). performed by a trained eye care pro- Women who develop vider. Retinal photography can also en- Screening strategies depend on the mellitus do not require an eye examination hance efficiency and reduce costs when rates of appearance and progression of during pregnancy and do not appear to be the expertise of ophthalmologists can diabetic retinopathy and on risk factors at increased risk of developing diabetic ret- be used for more complex examinations that alter these rates. While population- inopathy during pregnancy (28). Women and for therapy (32). In-person exams based studies often are the best source with preexisting type 1 or type 2 diabetes are still necessary when the retinal pho- for evaluating the rates of progression, whoplantobecomepregnantshouldhave tos are unacceptable and for follow-up if data from other studies, including ob- an ophthalmic examination prior to preg- abnormalities are detected. Retinal pho- servational studies and clinical trials, nancy and receive counseling about the tos are not a substitute for a compre- have provided important information risk of development and progression of di- hensive eye exam, which should be as well. A summary of screening recom- abetic retinopathy. When pregnant, an performed at least initially and at inter- mendations is in Table 3. eye examination should be performed dur- vals thereafter as recommended by an With regard to retinopathy onset, ing the first trimester with follow-up visits . Results of eye ex- vision-threatening retinopathy rarely scheduled depending on retinopathy se- aminations should be documented and appears in type 1 diabetes patients in verity (12,29). Rapid implementation of transmitted to the referring health care the first 3–5 years of diabetes or before tight glycemic control in the setting of ret- professional. puberty (22,23). Because retinopathy inopathycanbeassociatedwithworsen- takes at least 5 years to develop after ing of retinopathy (12). TREATMENT the onset of hyperglycemia, adults with For patients with diabetes, regular follow- Recommendations type 1 diabetes should have an initial up with early detection and treatment c Promptly refer patients with any dilated and comprehensive eye exami- of vision-threatening retinopathy enables level of macular edema, severe nation by an ophthalmologist or optom- the prevention of up to 98% of visual loss nonproliferative diabetic retinop- etrist within 5 years after the diagnosis due to diabetic retinopathy (30). The athy (a precursor of proliferative of diabetes. preventive effects of therapy and the diabetic retinopathy), or any pro- Up to one-fifth of patients with type 2 fact that patients with PDR or macular liferative diabetic retinopathy to diabetes have retinopathy at the time of edema may be provide an ophthalmologist who is knowl- first diagnosis of diabetes (24,25). Pa- strong support for screening to detect edgeable and experienced in the tients with type 2 diabetes who may diabetic retinopathy. management and treatment of di- have had years of undiagnosed diabetes An ophthalmologist or optometrist abetic retinopathy. A and have a significant risk of diabetic who is knowledgeable and experienced c Laser photocoagulation therapy retinopathy at the time of diagnosis in diagnosing diabetic retinopathy reduces the risk of vision loss in should have an initial dilated and com- should perform the examinations. If di- patients with high-risk prolifera- prehensive eye examination by an oph- abetic retinopathy is present, prompt tive diabetic retinopathy and, in thalmologist or optometrist at the time referral to an ophthalmologist is recom- some cases, severe nonprolifera- of diagnosis. mended. Comprehensive evaluation by tive diabetic retinopathy. A Subsequent examinations for patients an ophthalmologist will include dilated c Intravitreous injections of anti– with type 1 or type 2 diabetes are gener- slit-lamp examination including biomi- vascular endothelial growth factor ally repeated annually for patients with croscopy with a hand-held (90 or are indicated for central-involved diabetic macular edema, which oc- curs beneath the foveal center and Table 3—Screening recommendations for patients with diabetes may threaten reading vision. A Classification Examination by ophthalmologist or optometrist c The presence of retinopathy is Type 1 diabetes Within 5 years after onset of diabetes not a contraindication to aspirin Type 2 diabetes At time of diabetes diagnosis therapy for cardioprotection, as Women with preexisting diabetes planning Before pregnancy or in first trimester aspirin does not increase the risk pregnancy or who have become pregnant of retinal hemorrhage. A 416 Position Statement Diabetes Care Volume 40, March 2017

While optimization of blood glucose, data from the Diabetic Retinopathy Clin- severe vision loss in eyes affected with blood pressure, and serum lipid levels ical Research Network (DRCRN) suggest PDR (39). The benefit was greatest in conjunction with appropriately sched- that for eyes with CIDME and good levels among patients whose baseline evalua- uled dilated eye examinations can sub- of acuity, 20/40 or better, each agent tion revealed high-risk characteristics stantially decrease the risk of vision loss effectively and similarly improves visual (HRCs) consisting of disc neovasculari- from complications of diabetic retinopa- acuity. However, in eyes with CIDME and zation greater than or equal to one- thy, a significant proportion of those af- lower levels of acuity, 20/50 or worse, quarter of a disc area in size, any disc fected with diabetes develop DME or aflibercept appears to be most effective with vitreous hem- proliferative changes that require inter- at improving (38). Most orrhage, or vitreous hemorrhage with vention (Table 4). patients require near-monthly adminis- retinal neovascularization greater than tration of intravitreous therapy with anti- or equal to one-half of a disc area in CENTRAL-INVOLVED DME VEGF agents during the first 12 months of size. Although some eyes, especially Historically, focal laser photocoagula- treatment, with fewer injections needed in those of patients with type 2 diabetes, tion has been the standard treatment subsequent years to maintain remission benefit from early PRP prior to the de- for eyes with clinically significant macu- from CIDME. velopment of HRCs, given the risk of a lar edema (CSME), defined as either ret- Multiple emerging therapies for reti- modest loss of visual acuity and of con- inal edema located at or within 500 mm nopathy that target alternative pathways, traction of visual field from PRP, laser of the center of the macula or edema provide sustained intravitreous delivery of therapy has been primarily recom- of a disc area or more within a disc di- pharmacological agents, or allow oral or mended for eyes approaching or reach- ameter of the foveal center. The ETDRS topical noninvasive delivery systems are ing HRCs. (33) showed that treated eyes with currently under investigation for the treat- PRP is still commonly used to manage CSME had a significantly reduced risk ment of CIDME. Intravitreous steroid ther- eyes with PDR. However, widespread of further visual loss. apy for CIDME has been evaluated in observations that rapid regression of Current treatment thresholds are multiple phase 3 studies, and the steroid retinal neovascularization occurs in based on the presence of central- agents and fluocinolone eyes receiving intravitreous anti-VEGF involved DME (CIDME), or edema affect- acetonide are approved by the U.S. Food therapy for CIDME has made these ing the 1 mm in diameter retinal central and Drug Administration for the indication agents a potentially viable alternative subfield, rather than the presence of of CIDME. Nonetheless, given the inferior treatment for PDR. In a randomized trial CSME. Intravitreous therapy with agents visual acuity outcomes to anti-VEGF seen by the DRCRN comparing intravitreous that neutralize VEGF is currently the with intravitreous steroid therapy in a to PRP for visual acuity out- standard of care in the management of large DRCRN trial, as well as the increased comes in patients with PDR, there was eyes with CIDME, following numerous adverse events of cataract and glaucoma no statistically significant visual acuity well-designed randomizedphase3 clinical associated with steroid use, these agents difference between the ranibizumab trials that have shown benefit compared arerarelyusedasfirst-line therapy in eyes and PRP groups at 2 years (40). How- with monotherapy or even combination with CIDME. ever, average visual acuity outcomes therapy with laser (34–37). There are over the course of 2 years favored the currently three anti-VEGF agents com- PDR ranibizumab-treated group. Further- monly used to treat eyes with CIDMEd The Diabetic Retinopathy Study (DRS) more, significantly more eyes in the , ranibizumab, and afliber- showed that panretinal laser photoco- PRP group experienced peripheral visual cept. Of these anti-VEGF agents, recent agulation (PRP) reduced the risk of field loss and underwent for

Table 4—Recommended follow-up Referral to Indication ophthalmologist Follow-up Recommended intraocular treatment* No diabetic retinopathy Within 1 year Every 1–2 years None Mild NPDR Within 1 year Every year None Moderate NPDR Within 3–6 months Every 6–9 months None Severe NPDR Immediate Every 3–6 months Can consider early PRP for patients with type 2 diabetes PDR Immediate Every 3 months PRP or intravitreous anti-VEGF therapy, especially if HRCs are present No DME Within 1 year Every 1–2 years None Non-CIDME Within 3–6 months Every 6 months None, but observe carefully for progression to CIDME CIDME Immediate Every 1–4 months Anti-VEGF as first-line therapy for most eyes. Consider macularlaserasanadjunctivetherapyineyeswithpersistent CIDME despite anti-VEGF therapy. Intravitreous steroid treatment can be used as an alternative in selected cases. *In addition to optimizing systemic control of blood glucose, cholesterol, and hypertension, as well as educating the patient about importance of routine follow-up regardless of whether visual symptoms are present or absent. care.diabetesjournals.org Solomon and Associates 417

secondary complications of PDR than in looking at the latest advancement in ret- 5. Estacio RO, McFarling E, Biggerstaff S, Jeffers the ranibizumab group. In addition, inopathy treatment, anti-VEGF therapy. BW, Johnson D, Schrier RW. Overt albuminuria whereas 28% of eyes receiving PRP de- These eye injections have been shown predicts diabetic retinopathy in Hispanics with NIDDM. Am J Kidney Dis 1998;31:947–953 veloped DME over the course of 2 years, in numerous studies to be more cost- 6. Leske MC, Wu S-Y, Hennis A, et al.; Barbados Eye only 9% of ranibizumab-treated eyes did effective than laser monotherapy for DME Study Group. Hyperglycemia, blood pressure, and so. Only 6% of eyes in the ranibizumab (45–47). Future studies will be needed to the 9-year incidence of diabetic retinopathy: the group received PRP during the course of determine the cost-effectiveness of the Barbados Eye Studies. Ophthalmology 2005;112: – the study. Systemic safety outcomes ap- anti-VEGF medications as a first-line 799 805 7. Chew EY, Davis MD, Danis RP, et al.; Action to peared equivalent between the groups, treatment for PDR. Control Cardiovascular Risk in Diabetes Eye and injection-related Study Research Group. The effects of medical occurred in only one eye (0.5%) in the management on the progression of diabetic ret- ranibizumab group. Funding and Duality of Interest. S.D.S. re- inopathy in persons with type 2 diabetes: the These results suggest that intravitre- ceives academic support through the Katharine Action to Control Cardiovascular Risk in Diabe- tes (ACCORD) Eye Study. Ophthalmology 2014; ous anti-VEGF may be a viable alterna- M. Graham Professorship at Wilmer Eye Insti- tute, Johns Hopkins School of Medicine. E.C. is a 121:2443–2451 tive or adjunct to PRP for treatment of governmentemployee. L.S. didthe work without 8. UK Prospective Diabetes Study (UKPDS) eyes with PDR through at least 2 years. receiving any financial support from any third Group. Intensive blood-glucose control with sul- However, in applying these findings to partyandoverthe past36monthshasservedasa phonylureas or compared with conven- clinical practice, factors such as fre- consultant for Santen and Genentech. J.K.S. tional treatment and risk of complications in fi patients with type 2 diabetes (UKPDS 33). Lan- quency of follow-up, treatment cost, performed the work without any nancial sup- port from any third party; her relevant financial cet 1998;352:837–853 and patient preference must be consid- activities outside the submitted work over the 9. ACCORD Study Group, ACCORD Eye Study ered in addition to these safety and ef- last 36 months include research support from Group, Chew EY, et al. Effects of medical thera- ficacy outcomes. Complete application Genentech, Optovue, Boston Micromachines, pies on retinopathy progression in type 2 diabe- – of PRP can sometimes be accomplished Adaptive Sensory Technology, Optos, KalVista, tes. N Engl J Med 2010;363:233 244 and Roche, and she has received fees for con- 10. Do DV, Wang X, Vedula SS, et al. Blood pres- in as little as one visit, whereas intravit- sulting or invited talks from Allergan, Bayer, sure control for diabetic retinopathy. Cochrane reous ranibizumab may be required Eisai, Eleven Biotherapeutics, Kowa, Merck, Database Syst Rev 2015;1:CD006127 chronically, over numerous visits, to ad- Novartis, and Regeneron Pharmaceuticals. B.L.V. 11. Aiello LP, Gardner TW, King GL, et al. Diabetic equately maintain regression of PDR. receives financial support from National Institutes retinopathy. Diabetes Care 1998;21:143–156 12. Diabetes Control and Complications Trial Re- PRP costs less than a ranibizumab injec- of Health K23 Award (1K23EY025729-01). Addi- tional funding was provided by Research search Group. Effect of pregnancy on microvascular tion and carries no risk of endophthal- to Prevent Blindness and the Paul MacKall & complications in the Diabetes Control and Compli- mitis. However, if CIDME is present in an Evanina MacKall Foundation Trust as block cations Trial. Diabetes Care 2000;23:1084–1091 eye for which intravitreous anti-VEGF grants to the Scheie Eye Institute. C.C.W. is a 13. Goldstein DE, Blinder KJ, Ide CH, et al. Gly- therapy is planned, concomitant treat- consultant for Alimera Sciences, Allergan, Alnylam, cemic control and development of retinopathy in youth-onset insulin-dependent diabetes mel- ment with PRP may not be necessary, as Bayer, Clearside Biomedical, DORC, Genentech, ONL Therapeutics, Regeneron Pharmaceuticals, litus. Results of a 12-year longitudinal study. the anti-VEGF agent will likely effec- Thrombogenics, and Valeant; has minor equity in Ophthalmology 1993;100:1125–1131; discus- tively manage both the CIDME and the ONL Therapeutics; receives research support from sion 1131–1132 PDR. Allergan, Apellis Pharmaceuticals, Clearside Bio- 14. Rashid S, Young LH. Progression of diabetic medical, Iconic Therapeutics, Genentech, Regeneron retinopathy and after phacoemul- fi COST-EFFECTIVENESS OF Pharmaceuticals, Diabetic Retinopathy Clinical Re- si cation surgery. Int Ophthalmol Clin 2010;50: search Network, Ophthotech, ThromboGenics, and 155–166 SCREENING AND TREATMENT FOR Tyrogenex; and has been a speaker for Allergan 15. Sun JK, Radwan SH, Soliman AZ, et al. Neu- DIABETIC RETINOPATHY and Regeneron Pharmaceuticals. T.W.G. is a ral retinal disorganization as a robust marker of The cost-effectiveness of both screening consultant for Novo Nordisk, KalVista, Janssen visual acuity in current and resolved diabetic and traditional laser treatment for dia- Research, PureTech Health, Johnson & Johnson, macular edema. Diabetes 2015;64:2560–2570 and BetaStem, which have no relationship to this 16. Klein R, Knudtson MD, Lee KE, Gangnon R, betic retinopathy has been established manuscript. No other potential conflicts of inter- Klein BEK. The Wisconsin Epidemiologic Study of long ago and is no longer in dis- est relevant to this article were reported. Diabetic Retinopathy: XXII the twenty-five-year pute. More recent literature on cost- progression of retinopathy in persons with type 1 effectiveness has now focused on the References diabetes. Ophthalmology 2008;115:1859–1868 impact of telemedicine on the detection 1. American Diabetes Association. Diabetic reti- 17.KleinR,KleinBE,MossSE,Cruickshanks KJ. 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