Catherine Creuzot-Garcher Patricio Schlottmann Adnan ... · Adnan Tufail The burden of diabetes is expected to increase significantly over the coming decades with a pro-jected 700

Supplement to November/December 2020S P O N S O R E D B Y

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Let’s Discuss Diabetic Eye Disease

Catherine Creuzot-Garcher Dijon University Hospital, Dijon, France

Patricio Schlottmann Organizacion Medica de Investigacion, Buenos Aires, Argentina

Adnan Tufail Moorfields Eye Hospital NHS Foundation Trust, London, United Kingdom

Paul Mitchell Centre for Vision Research, The Westmead Institute for Medical Research, The University of Sydney, Sydney, Australia

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This supplement features summaries of presentations from a Novartis-sponsored symposium at the 2020 virtual EURETINA congress in which expert retinal specialists discuss important and timely topics relating to the management of patients with diabetic eye disease.


CATHERINE CREUZOT-GARCHERn Dijon University Hospital, Dijon, France n Financial disclosure: Allergan, Bayer, Novartis, Roche,

Thea, Horus

PATRICIO SCHLOTTMANNn Organizacion Medica de Investigacion, Buenos Aires, Argentinan Financial disclosure: Consultant (Allergan, Novartis, Roche);

speaker (Novartis, Roche)

ADNAN TUFAILn Moorfields Eye Hospital NHS Foundation Trust, London,

United Kingdomn Financial disclosure: None acknowledged

PAUL MITCHELLn Centre for Vision Research, The Westmead Institute for Medical

Research, The University of Sydney, Sydney, Australian Financial disclosure: None acknowledged

Page

2 Diabetic Eye Disease: Treat the Eye or the Body? Catherine Creuzot-Garcher

4 DR Screening Programs: Preventing Vision Loss? Adnan Tufail

5 DME Management: What Have We Learnt? Patricio Schlottmann

7 How Will COVID Influence the Future Management of Diabetic Eye Disease? Moderated by Paul Mitchell

Paul Mitchell“Diabetes is a cause for serious concern,” said Prof. Paul

Mitchell. “We know that this disease is going to be one of the defining diseases of the current century.” In 2019, 463 million adults worldwide were living with diabetes. Of these, around 140 million had some form of diabetic retinopathy (DR), which was vision-threatening in 14 million individuals.1 These numbers are only expected to increase in the coming years,1 making diabetic eye disease an important topic of discussion for general ophthalmologists and retinal specialists alike.

Diabetic Eye Disease: Treat the Eye or the Body?

Catherine Creuzot-Garcher“In diabetic eye disease, it is important to

treat both the eye and the diabetic patient as a whole,” said Prof. Catherine Creuzot-Garcher. “Patients with diabetes have a complex range

of comorbidities associated with their condition. Around 30% are overweight or obese, two-thirds have hypertension, and a quarter have cardiovascular disease.”2 Other potential complications include cerebrovascular accident, diabetic nephropathy, dyslipidemia, diabetic neuropathy, and DR.2

Patients with diabetic eye disease may be at a particularly high risk of diabetes-associated complications. Patients with diabetic macular edema (DME) and/or DR are more likely to have stroke and myocardial infarction than age- and gender-matched subjects

Figure 1. Quality of life (QoL) in patients with DME and DR.

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with diabetes without ophthalmic manifestations, retinal disorders, or vitreous hemorrhage.3 The prevalence of DME differs according to the type of diabetes and the treatment that the patient is undergoing, and it is higher in patients with type 1 diabetes than in those with type 2 diabetes taking insulin, who in turn have a higher prevalence than patients with type 2 diabetes who are not taking insulin.4 The 25-year cumulative incidences of DME and clinically significant macular edema are 29% and 17%, respectively, in patients with type 1 diabetes.4

Diabetic eye disease, particularly DME, has a negative impact on patient quality of life. In a prospective observational study, scores on the National Eye Institute 25-item Visual Function Questionnaire were significantly poorer in type 2 diabetes patients with DME compared with type 1 patients with DR (P < .01 on all items other than ocular pain, for which the comparison was not significantly different; Figure 1).5 Indeed, loss of vision is the most feared complication of diabetes, ahead of cardiac disease, renal problems, circulation problems, and problems with the feet or legs (Figure 2).6

Effective management of diabetes, including diabetic eye disease, requires a multidisciplinary, patient-centric approach. This should aim to treat multiple targets (e.g. HbA1c, blood pressure, lipids, and body weight), provide ongoing medical and psycho-behavioral support, and help patients achieve self-management of their condition.1 Individual-level care can be assessed at a system and country level using population-based surveys and hospitalization

and mortality data in order to guide administrative decision-making and policy implementation toward areas of greatest need.1

There are a number of constraints to the effective manage-ment of DR and DME, from both the clinician and patient per-spectives. Clinicians are challenged with managing wide variations in patient responses to treatment, the complex comorbidity profile of the high-risk population, and the suboptimal outcomes associated with delayed initiation of treatment with anti-VEGF therapy.7,8 Meanwhile, patient challenges include compliance to treatment and monitoring schedules, the cost of treatment and/or medical insurance, the burden associated with long-term follow-up and management, problems with access to health care and treatment, and the time spent on treatment, visits, and follow-up, particularly for the working-age population.7-9

The challenge of patient compliance, in particular, can sig-nificantly impact outcomes. A retrospective multicenter study reviewed data from 12 patients with proliferative DR (PDR) or nonproliferative DR (NPDR) with or without DME, treated exclusively with anti-VEGF therapy, who were lost to follow-up for a mean of 13.3 months.10 Upon examination on their return to the clinic, these patients had an average worsening in visual acuity from a mean of 0.61 logMAR before the interruption in treatment to 1.53 logMAR at their final visit (Figure 3). Reasons provided for the treatment hiatus included intercurrent illness, non-compliance, and financial issues.10 “It seems that some patients are lost to follow-up not because they are not interested in attending clinic visits, but because they are not able to attend,” said Prof. Creuzot-Garcher. “That is why we need to consider a number of different interconnecting factors in order to improve patient care, including social support from family and peers, control of systemic factors with medication and lifestyle changes, support to promote healthy eating, and regular medical examina-tion to enable early detection and timely treatment of diabetic eye disease.” It is recommended that diabetic patients with no signs of DR, or with mild PDR only, are examined annually. Those with moderate NPDR should be examined every 6 months, those with any PDR and macular edema once every 3 months, and those at highest risk (young diabetic patients, pregnant patients, those undergoing cataract surgery, or those with nephropathy) should be seen at least once every 3 months or more frequently.

Figure 2. Patients’ opinions on the complications of diabetes.

Figure 3. Investigating treatment interruption in patients with PDR or NPDR with or without DME.

Highlights• Diabetes is a complex disease associated with a range of comorbidities.• Loss of vision is the most feared complication of diabetes and dia-

betic eye disease has a significant negative impact on patient QoL.• Effective management of diabetes and diabetic eye disease

requires a multidisciplinary, patient-centric approach.• There are a number of constraints to the effective management

of DR and DME, of which patient compliance is particularly challenging and may negatively impact visual outcomes.

• Patients with diabetes, particularly those with signs of DR, should be examined on a regular, scheduled basis.



DR Screening Programs: Preventing Vision Loss?

Adnan TufailThe burden of diabetes is expected to increase significantly over the coming decades with a pro-jected 700 million diabetic adults and 21 million individuals with vision-threatening DR in 2045.1

In order to manage this huge burden, effective screening for DR is critical. “The challenge is to identify these patients at an appropriate time when the available treatments for proliferative disease and DME can be most effective,” said Mr. Adnan Tufail. “This means detecting disease before significant visual loss occurs, namely when the patient is asymptomatic.”

Comprehensive screening for DR is not yet standard in health care systems worldwide, but an example of a large-scale DR screening success story comes from the United Kingdom. The English National Health Service (NHS) Diabetic Eye Screening Program commenced in 2003.11 It followed several key princi-ples of screening: that screening is a public health program rath-er than a diagnostic test; that it should include large numbers of apparently healthy individuals who are offered further diag-nostic investigation, if their screening test is positive; and that it should achieve the highest possible standards, which should be ensured using quality assurance to reduce the probability of error and risk. The NHS Diabetic Eye Screening Program offers two-field mydriatic digital photographic screening annually to all individuals with diabetes aged 12 years and over. By 2008 the program had reached population coverage, and by 2015-2016, 2.59 million patients with diabetes were offered screening and 2.14 million received it.11 The impact of this screening program has been a reduction in blindness due to DR in the United Kingdom, a reduced number of vitrectomies, and DR/maculop-athy no longer being the leading cause of certifiable blindness in the working age population (Figure 4).11

However, such successful, large-scale screening programs result in millions of images each year that currently require manual grading by trained human graders, a process that is

both labor- and capital-intensive (Figure 5).12 Automation of the image analysis process has the potential to reduce the bur-den of DR screening. Automated retinal image analysis systems (ARIAS) allow the detection of DR without requiring a human grader. The diagnostic accuracy of these systems has been reported to be comparable to that of a human grader, with a high degree of sensitivity.12 They have the potential to increase the efficiency, reproducibility, and coverage of screening pro-grams.13 However, to be implemented, it must be ensured that ARIAS are independently validated, able to perform in a real-life and high volume setting, and are safe and cost-effective.

In order to determine whether ARIAS can be safely intro-duced into DR screening pathways to replace human graders, an observational study included retinal images from 20,258 consecutive patients attending routine annual diabetic eye screenings.12 It compared the results of manual grading of these images following a standard national protocol with grading by three different ARIAS (iGradingM, Retmarker, and EyeArt). Discrepancies between manual grades and ARIAS results were sent to a reading center for arbitration, and the screening performance (i.e. sensitivity) and diagnostic accuracy (95% CI of the screening performance measures) were determined. Sensitivity point estimates (95% CI) of the ARIAS were, for EyeArt, 94.7% (94.2-95.2%) for any retinopathy, and 99.6% (97.0-99.9%) for proliferative retinopathy; and for Retmarker, 73.0% (72.0-74.0%) for any retinopathy and 97.9% (94.9-99.1%) for proliferative retinopathy.12 iGradingM classified all images as either having disease or being ungradable, due to an incom-patibility between the software and the type of image used for analysis. “The Retmarker and EyeArt systems achieved accept-able sensitivity when compared with human graders, with suffi-cient specificity to make them cost-effective alternatives,”12 said Mr. Tufail.

In addition to traditional screening programs where diagnos-tic testing is performed in the ophthalmologist’s clinic, there may be valuable roles for telemedicine and home monitoring in the prevention of vision loss due to DR. Telemedicine, where digital images are captured at primary care or mobile clinics and sent for interpretation by an ophthalmologist at another Figure 4. The English NHS Screening Program for Diabetic Retinopathy.

Figure 5. The burden of manual image grading.



location, has been shown to help to increase DR screening rates, adherence, and disease awareness, particularly in remote and underserved areas.14-18 Telemedicine is cost-effective and associ-ated with high levels of patient satisfaction, although its suc-cess is dependent on having the required technology, internet access, and infrastructure in place.14-18

Like telemedicine, home monitoring could help to increase compliance and prevent vision loss through early detection of DR allowing prompt, targeted treatment (Figure 6). Patients with diabetes are already accustomed to monitoring other aspects of their disease, such as blood glucose levels and foot health.19-22 Monitoring of vision using the Amsler grid test, home OCT and smartphone-based visual acuity measure-ment,23 or detection of biomarkers of DR using simple urine-based assays,24 could extend this self-monitoring to the visual complications of diabetes. With home monitoring, patients feel more involved in and responsible for the management of their condition whilst benefiting from the convenience of not having to leave home.23 However, effective home monitoring requires patient education, and tests must be easy to perform and pro-vide reproducible results.20,21,23

DME Management: What Have We Learnt? Patricio Schlottmann

A comparison of data from key clinical trials of anti-VEGF therapy in DME shows that similar visual acuity scores are achieved at 12 months

regardless of the dosing regimen or anti-VEGF agent (Figure 7).25-

30 “Something that most of these trials have in common is that, while lower baseline visual acuities are associated with greater visual gains, overall final vision is subject to a ceiling effect such that an absolute visual acuity of around 70 letters is generally achieved,” said Prof. Patricio Schlottmann.

The ceiling effect is also apparent in real-world evidence from observational studies. Similar visual acuity gains were observed with ranibizumab and aflibercept, and absolute visual acuity scores trended towards the 70-letter level (Figure 8).31-35 An exception to the ceiling effect observation is the Protocol T study, where visual acuity gains at 12 months were unusually high in all three study arms (13.3, 11.2, and 9.7 letters for aflibercept 2 mg, ranibizumab 0.3 mg, and bevacizumab 1.25 mg, respectively) despite patients having rela-tively good vision at baseline and the dose of ranibizumab used being lower than that approved for use in DME in all regions outside the United States.30

Highlights• DR is a growing health concern, expected to threaten the vision of

21 million individuals by 2045.• There is a need for effective DR screening that identifies patients at

a stage where treatment can be most impactful. • The English NHS Diabetic Eye Screening Program is a good example

of a successful large-scale DR screening program that reduced the prevalence of blindness due to DR in the United Kingdom.

• Automated retinal image analysis may allow the detection of DR without requiring human graders, increasing the efficiency, reproducibility, and coverage of screening programs.

• Telemedicine and home monitoring may also have a role in the prevention of vision loss due to DR.

Figure 6. Telemedicine and home monitoring for diabetic eye disease.

Figure 7. Visual acuity outcomes in key clinical trials of anti-VEGF therapy in DME.

Figure 8. Real-world outcomes with ranibizumab and aflibercept.



Patients with poor baseline vision are likely to have the largest visual acuity gains upon treatment with anti-VEGF therapy, as shown in the Protocol I and Protocol T studies in which patients with baseline VA of 20/50 or worse achieved final visual acuity gains of between 10 and 18 letters.36,37 However, early treatment is still preferable, as the final visual status of these patients may still not equal that of patients whose visual acuity was not permitted to decline to the same extent before treatment. In the case of patients with good baseline vision and center-involving macular edema, observation without treatment might be a reasonable approach.38 In the Protocol V study, there were no significant differences in the rates of vision loss at 2 years between aflibercept and observation in patients with baseline VA of 20/25 or better and center-involving macular edema.38

The LUMINOUS observational study has demonstrated that real-world outcomes with ranibizumab in treatment-naïve DME patients are better in those that receive initial intensive therapy. Patients who received a loading dose of three initial consecutive ranibizumab injections at 4-weekly intervals had consistently better visual acuity gains at 1 year than those who did not receive a loading dose, even in those patients who received a relatively high number of injections (eight or more) over the course of that year (Figure 9).39

Extensive clinical trial evidence from the RISE and RIDE,25,40,41 Protocol I,27,36,42,43 RESTORE,28,44,45 RETAIN,26 REFINE,46 and REVEAL47 studies is available to support the efficacy of ranibizumab 0.5 mg for the treatment of DME, demonstrating early visual acuity gains that are sustained over time. Patients in RISE and RIDE maintained gains of 11.2 letters at 3 years, following initial 2-year gains of 12.0 let-ters.25,40,41 In the RESTORE study, patients treated with ranibizumab achieved rapid visual acuity gains of 7.9 letters at 12 months that were sustained at 3 years.44 Similarly, patients in the Protocol I study maintained vision gains over 5 years, with a mean gain of 9.8 letters at 5 years for patients in the ranibizumab plus deferred laser group.36

In both RESTORE and Protocol I, long-term follow-up reveals that the required injection frequency in patients with DME reduces mark-edly over time. Patients in RESTORE received a mean of 7.4 injections in year 1 but required just 2.9 injections in year 3,44 while patients in the ranibizumab plus deferred laser arm of the Protocol I study received a median of nine injections in year 1 which reduced to zero injections in year 5.36 “It seems that, if an adequate number of injec-tions are provided in the first year, the patient will probably need

half of that in the second year, then half of that again in the third year, and probably no injections in the fourth and fifth year. This is a very important take-home message for managing your patients with DME,” said Prof. Schlottmann.

Considering the use of laser therapy in the RESTORE study, visual outcomes were significantly inferior for patients in the laser monotherapy arm compared with those treated with ranibizumab or ranibizumab plus laser.28 This was observed in all subgroups of patients stratified by baseline BCVA, but was particularly notable in those patients with better vision at baseline (BCVA greater than 73 letters), in whom laser therapy resulted in the loss of a line of vision at 12 months.28

In most of the pivotal trials of ranibizumab and aflibercept in DME, dosing was provided according to a fixed or PRN regimen. However, the RETAIN study provides valuable evidence on the use of ranibizumab for DME in a treat-and-extend (T&E) regimen. In RETAIN, over 70% of patients receiving ranibizumab according to a T&E regimen were able to maintain visual acuity with a treat-ment monitoring interval of 2 months or more (Figure 10).26,48 In addition, the T&E regimen resulted in a 46% reduction in patient monitoring visits between months 3 and 24 of the trial compared with a PRN regimen.26

Figure 9. Visual acuity outcomes with and without a loading dose in the LUMINOUS study.

Figure 10. Patient monitoring visits and treatment intervals in the RETAIN study.

Highlights• In clinical trials of anti-VEGF therapy in DME, similar visual acuity

scores of around 70 letters are achieved at 12 months regardless of the dosing regimen or anti-VEGF agent.

• Patients with poor baseline vision are likely to achieve the largest visual acuity gains upon treatment with anti-VEGF therapy, but early treatment is still important to ensure good final visual acuity.

• Initial intensive therapy, including a loading dose of three monthly injections, provides the best visual outcomes.

• Ranibizumab treatment can provide early visual acuity gains that are sustained over time. The required injection frequency in patients with DME reduces markedly over time.

• A T&E regimen in DME allows visual acuity gains to be maintained with extended treatment intervals and a reduction in patient monitoring visits compared with PRN dosing.



How Will COVID Influence the Future Management of Diabetic Eye Disease?

Moderated by Paul MitchellProf. Paul Mitchell leads a discussion on the

challenges posed by the COVID-19 pandemic to the management of diabetic eye disease, consider-ing measures to protect patients, the clinician, the

ophthalmologist, and other staff while managing treatment to reduce the impact of COVID-19 on patients’ vision.

How can we manage our practices during the pandemic to best protect patients?

Prof. Schlottman: Our approach is to wear personal protec-tive equipment, ensure that patients are wearing masks at all times, and reduce the time that patients spend in the clinic, including waiting times. We also minimize the procedures that are performed: in some situations, we may skip visual acuity mea-surement and as a surrogate measure ask the patient how their vision is. We perform OCT in patients where we want to evaluate the stage of macular edema, but otherwise, if the patient is well controlled and receiving injections with T&E, we maintain the maximum treatment interval that we have achieved, provide the injection, and schedule the patient for a future visit. If a patient needs treatment for both eyes, we try to give bilateral injections in the same visit.

How can we protect clinicians, ophthalmologists, and staff at this time?

Prof. Creuzot-Garcher: We try to avoid any examinations that require contact and instead use alternative technologies such as wide-field imaging and OCT. Where contact is necessary, for example in patients with PDR who require laser treatment, we perform it within two sequences in order to avoid the patient having to move too much through the department.

How can treatment be managed to help to reduce contact with patients?

Mr. Tufail: Patients that have severe NPDR or low-risk proliferative disease but do not need immediate active treatment are put into an imaging pathway with high-resolution wide-field cameras plus OCT. They are reviewed the same day and, if they need treatment, then they see the physician. If the patient is already on a treatment schedule, they might attend a regular injection visit to receive one of a run of three injections or be treated according to a T&E approach. Bilateral treatments are given, if necessary, to minimize the number of patient visits. We are also exploring an extension of primary screening which filters patients with referable macular edema from those who are non-referable (i.e. those with no or mild DR and no macular edema) and enters them into a screening clinic within the hospital.

In patients who have missed visits because of COVID-19, have you seen many who have developed more severe disease and vision loss as a result of this?

Mr. Tufail: The impression of myself and many of my fellow consultants is that this has indeed happened due to suspension of the primary screening program. We continued to invite patients who were identified as having low-risk PDR or very severe NPDR to come to the hospital, but otherwise many patients didn’t come for screening due to concerns about their risk of complications, if they were to develop COVID-19. This was a particular concern since we are based in central London and patients would have had to use public transport. This meant that many patients had DR progression without detection. We are now seeing a flurry of patients with vitreous hemorrhage and rubeosis that we think is just prevalent, untreated disease.

Prof. Schlottman: We have seen a 20% loss of patients to follow-up. In the coming months, I expect to be able to see these patients, who hopefully will not have progressed too much. n

Closing commentsPaul MitchellIn conclusion, the effective management of diabetes and diabetic eye disease requires a multidisciplinary approach which considers the whole individual.1 However, this can be challenging for both the physician and the patient.7-9 Ensuring compliance is a particular difficulty that can significantly impact visual outcomes.10 Effective DR screening programs can enable earlier diagnosis and treatment and can reduce the amount of blindness due to DR.11 The use of innovative automated technologies may increase their efficiency, reproducibility, and coverage.12,13 Telemedicine and home monitoring systems may also play a role in improving patient outcomes.14-18,23,24

A wealth of clinical trial and real-world evidence supports the use of anti-VEGF therapy in DR and DME, including long-term data up to 5 years.25-28,36,40-47 Early intensive treatment that includes a loading dose provides the greatest gains in visual acuity and allows for a reduced treatment burden over time.36,39,44 A T&E approach in DME facilitates reduced visits and can optimize clinic efficiency.26,48 “Finally, practical clinical considerations are key to managing diabetic eye disease and protecting patients and staff given the current COVID-19 situation,” said Prof. Mitchell.



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26. Prunte C, Fajnkuchen F, Mahmood S, et al. Ranibizumab 0.5 mg treat-and-extend regimen for diabetic macular oedema: the RETAIN study. Br J Ophthalmol . 2016;100:787-795.27. Elman MJ, Aiello LP, Beck RW, et al. Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology . 2010;117:1064-1077 e35.28. Mitchell P, Bandello F, Schmidt-Erfurth U, et al. The RESTORE study: ranibizumab monotherapy or combined with laser versus laser monotherapy for diabetic macular edema. Ophthalmology . 2011;118:615-625.29. Korobelnik JF, Do DV, Schmidt-Erfurth U, et al. Intravitreal aflibercept for diabetic macular edema. Ophthalmology . 2014;121:2247-2254.30. Diabetic Retinopathy Clinical Research N, Wells JA, Glassman AR, et al. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. N Engl J Med . 2015;372:1193-1203.31. Bhandari S, Nguyen V, Fraser-Bell S, et al. Ranibizumab or aflibercept for diabetic macular edema: comparison of 1-year outcomes from the Fight Retinal Blindness! registry. Ophthalmology . 2020;127:608-615.32. Epstein D, Amren U. Long-time outcome in patients treated with ranibizumab for diabetic macular edema: a 4-year study. Retina . 2018;38:183-186.33. Korobelnik JF, Daien V, Faure C, et al. Real-world outcomes following 12 months of intravitreal aflibercept monotherapy in patients with diabetic macular edema in France: results from the APOLLON study. Graefes Arch Clin Exp Ophthalmol . 2020;258:521-528.34. Stefanickova J, Cunha-Vaz J, Ulbig M, et al. A noninterventional study to monitor patients with diabetic macular oedema starting treatment with ranibizumab (POLARIS). Acta Ophthalmol . 2018;96:e942-e949.35. Massin P, Creuzot-Garcher C, Kodjikian L, et al. Real-world outcomes with ranibizumab 0.5 mg in patients with visual impairment due to diabetic macular edema: 12-month results from the 36-month BOREAL-DME study. Ophthalmic Res . 2019;62:101-110.36. Elman MJ, Ayala A, Bressler NM, et al. Intravitreal ranibizumab for diabetic macular edema with prompt versus deferred laser treat-ment: 5-year randomized trial results. Ophthalmology . 2015;122:375-381.37. Wells JA, Glassman AR, Ayala AR, et al. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema: two-year results from a comparative effectiveness randomized clinical trial. Ophthalmology . 2016;123:1351-1359.38. Baker CW, Glassman AR, Beaulieu WT, et al. Effect of initial management with aflibercept vs laser photocoagulation vs observation on vision loss among patients with diabetic macular edema involving the center of the macula and good visual acuity: a randomized clinical trial. JAMA . 2019;321:1880-1894.39. Mitchell P, Sheidow TG, Farah ME, et al. Effectiveness and safety of ranibizumab 0.5 mg in treatment-naive patients with diabetic macular edema: Results from the real-world global LUMINOUS study. PloS one . 2020;15:e0233595.40. Brown DM, Nguyen QD, Marcus DM, et al. Long-term outcomes of ranibizumab therapy for diabetic macular edema: the 36-month results from two phase III trials: RISE and RIDE. Ophthalmology . 2013;120:2013-2022.41. Boyer DS, Nguyen QD, Brown DM, et al. Outcomes with as-needed ranibizumab after initial monthly therapy: long-term outcomes of the Phase III RIDE and RISE trials. Ophthalmology . 2015;122:2504-2513 e1.42. Elman MJ, Bressler NM, Qin H, et al. Expanded 2-year follow-up of ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology . 2011;118:609-614.43. Elman MJ, Qin H, Aiello LP, et al. Intravitreal ranibizumab for diabetic macular edema with prompt versus deferred laser treatment: three-year randomized trialrResults. Ophthalmology . 2012;119:2312-2318.44. Schmidt-Erfurth U, Lang GE, Holz FG, et al. Three-year outcomes of individualized ranibizumab treatment in patients with diabetic macular edema: the RESTORE extension study. Ophthalmology . 2014;121:1045-1053.45. Lang GE, Berta A, Eldem BM, et al. Two-year safety and efficacy of ranibizumab 0.5 mg in diabetic macular edema: interim analysis of the RESTORE extension study. Ophthalmology . 2013;120:2004-2012.46. Li X, Dai H, Li X, et al. Efficacy and safety of ranibizumab 0.5 mg in Chinese patients with visual impairment due to diabetic macular edema: results from the 12-month REFINE study. Graefes Arch Clin Exp Ophthalmol . 2019;257:529-541.47. Ishibashi T, Li X, Koh A, et al. The REVEAL study: ranibizumab monotherapy or combined with laser versus laser monotherapy in Asian patients with diabetic macular edema. Ophthalmology . 2015;122:1402-1415.48. Galvez ML. Data presented at World Ophthalmology Congress. 2018.

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