Diabetes mellitus (DM) is one of the world's fastest growing chronic diseases. It is estimated to double from 171 million in the year 2000 to 366 million by the year 2030.1 With the increasing prevalence of diabetes, the number of diabetes retinopathy (DR) and vision-threatening DR, which includes severe nonproliferative DR, proliferative DR, and diabetic macular edema (DME), is expected to reach 191.0 million and 56.3 million, respectively, by 2030.1 The increase in diabetic population in Asia is anticipated to be more severe than the average global increase. The factors attributing to this include poor access or lack of screening services resulting in late presentation, earlier onset of diabetes, that is, younger population becoming diabetic, poor compliance, and poor understanding of DM due to lack of health education.2
DME is one of the main causes of vision loss in patients with diabetes mellitus. Management of DME focuses on improving anatomical parameters such as reducing central macular thickening (CMT) and functional parameters such as improving visual acuity (VA).3 Over the past decade, advances in DME research have introduced anti-vascular endothelial growth factor (anti-VEGF) agents and corticosteroid injections as leading treatment options. This has progressed from conventional treatment of laser photocoagulation and vitrectomy.4 The current treatment guidelines recommend anti-VEGF drugs as the first-line therapy in most cases.5 Although ranibizumab, aflibercept, and off-label use of bevacizumab have shown good results in the management of DME,6 at least 40% of patients show suboptimal anatomical and/or functional responses to these drugs.7 Corticosteroids such as dexamethasone and fluocinolone acetonide have demonstrated good efficacy and safety profiles in the treatment of DME.8 Despite these advances, there is a lack of comprehensive guidelines on the use of appropriate first-line agents, identifying responders, appropriate time to switch treatment modalities, patient profiling to manage possible side effects, and uncommon complications.
Recently, in Europe, several expert panels have attempted to address various issues pertaining to the management of DME. Kodjikian et al9 provide an algorithm for suitable first-line treatment in center involving DME. The MOMEMTUM-D group published recommendations for the use of intravitreal dexamethasone implants in DME.10 However, there are insufficient evidence-based consensus guidelines for the Asian epidemiology in the management of DME. Cheung et al published one of the first recommendations for managing DME in Asian countries. Nevertheless, this specifically focused on providing clinical evidence-based guidelines for the use of anti-VEGF agents.11
This consensus article aims at providing comprehensive recommendations in the management of DME in the Asia-Pacific region. The main aspects these guidelines address are: identifying the types of responders for anti-VEGF agents, determining the appropriate time to switch when required, identifying cases where intravitreal dexamethasone can be considered and administered as first-line, and providing evidence-based management considerations for potential complications from intravitreal dexamethasone use, that is, intraocular pressure (IOP) rise and cataract progression.
A questionnaire comprising of 4 sections: defining treatment response to anti-VEGF therapy, steroid treatment options, steroid use and side effects, and cost and compliance/reimbursement models, was developed using the Delphi questionnaire published in 2017 as a guide.12 A total of 47 questions were developed on the above-mentioned sections. An expert panel of 12 retinal specialists from Singapore, Malaysia, the Philippines, India, and Vietnam responded to the questionnaire at 2 separate occasions in masked fashion. Each member was an active medical retina consultant with vast experience (more than 10 years of clinical practice) in DME management within the Asia-Pacific clinical settings, and in participation of DME research. Since this study did not include patient information, the internal review board approval was exempted.
On the first occasion, panellists provided anonymous answers to the questionnaire. These were compiled, analyzed, and explored at a round table discussion held on June 15, 2019. During the round table discussion, the results of the questionnaire were discussed, individual opinion was recorded, and consensus was sought through voting. Consensus on any recommendation was considered “achieved” when 9 of the 12 panellists (75%) were in agreement. Table 1A and B, Table 2A and B, and Table 3A provided the list of recommendation from each of the respective sections and the corresponding consensus results.
DME Treatment Protocol
To develop the recommendations, the DME patients were profiled based on the type of response to treatment. The terms target response, adequate response, nonresponse, and inadequate response were defined as follows:
- i. Target response: 6/6 or CMT of < 300 μm.
- ii. Adequate response is defined as 6/12 or better and CMT <300 μm, or improvement in CMT as a percentage (>10%) after treatment (those who achieved are responders).
- a. Inadequate response is defined as response <6/6 and CMT still >300 μm or change in CMT <10% after 1 to 3 anti-VEGF injections.
- b. Nonresponse is defined as response <6/6 and CMT still >300 μm or change in CMT <10% after 3 injections.
The recommendations derived from each section of the questionnaire were summarized into an algorithm to provide a simple treatment guideline to clinicians for the management of DME (Fig. 1).
The algorithm is explained briefly in the following points:
- First-line treatment for different conditions of DME are as follows:
- a. Anti-VEGF: Symptomatic center involving DME (defined as edema within 100 μm of the center of fovea), persistent DME (inadequate or nonresponse as defined above), phakic patients: <60 years old and patients with glaucoma.
- b. Intravitreal steroid (dexamethasone): Intravitreal corticosteroids may be considered in patients with the following conditions—patients with high-risk cardiovascular disease, patients with poor compliance, severe edema (>500 μm),4 pseudophakic patients, patients scheduled to undergo cataract surgery, and patients with a history of vitrectomy. In patients with stable glaucoma, steroids may be considered. ∗Refer to glaucoma recommendations (Fig. 2).
- c. Focal laser: For noncenter involving DME (which was defined by the consensus group as edema outside 100 μm diameter of the center of fovea and/or meeting Early Treatment Diabetic Retinopathy Study—Clinically Significant Macular Edema (ETDRS CSME) definition.4
- d. Trans pars plana vitrectomy with membrane peeling with or without adjunctive intravitreal steroid treatment: in cases of tractional macular edema.
- Anti-VEGF treatment should be administered monthly for 3 to 6 months and follow-up management should be carried out 1 month after 3 injections.
- ∘ If the response is adequate, treatment should be continued.
- ∘ If response is inadequate, consider switching to alternative treatment modalities such as other anti-VEGF agents or steroids.
- ∘ If no response, consider switching to steroid (dexamethasone) especially in case of pseudophakic patients.
- ∘ During follow-up assessment, if DME remains stable post 3 to 6 injections (stability defined as no change in VA. Less than 10% change in central macular thickness on optical coherent tomography (OCT) after 2 consecutive injections) can consider treat and extend regime.
- Intravitreal steroid treatment, appropriate counseling for possible side effects should be provided to the patients.
- ∘ Routine, uncomplicated patients with no other ocular comorbidities should be reviewed at 6 weeks post-injection for IOP check and subsequently, followed-up at months 2 to 3 post-treatment. Depending on the response, retreatment may be considered on a 4 to 6 monthly basis.
- ∘ If the response is adequate, continued assessment and treatment at 4 to 6 monthly intervals may be considered while monitoring side effects and contraindications.
- ∘ If response is inadequate or no response, switch to anti-VEGF.
For all treatment modalities, if there is no worsening and/or improvement in DME is observed, follow-up duration can be doubled to 4 months and a “defer and extend” approach can be considered.
Treatment Recommendations in Glaucoma Patients Treated With Dexamethasone13
Based on the history of glaucoma, patients are divided into 4 groups (Fig. 2):
- Group I are patients who do not have any history of IOP issues. These patients can be assessed at weeks 1, 2, and 4 to 6 weeks post-treatment and antiglaucoma medication is initiated if IOP ≥28 mm Hg.
- Group II are patients with history of steroid response or ocular hypertension. In this group, antiglaucoma medication should be used before initiation of intravitreal steroid treatment and/or as post-treatment regimen. They are assessed at weeks 1 and 2 post-treatment for IOP checks.
- Group III are patients with controlled glaucoma. Antiglaucoma treatment should be maintained throughout intravitreal dexamethasone treatment period. If IOP is not controlled, dexamethasone treatment is discontinued and referral to glaucoma specialists should be considered.
- Group IV are patients who have developed glaucoma secondary to intravitreal dexamethasone treatment. In this scenario, patients are treated with antiglaucoma therapy and referral to glaucoma specialist should be made. Intravitreal dexamethasone is discontinued until IOP is controlled and glaucoma is stable.
Recommendations to Treat IOP Pressure Spike and Glaucoma
Rise in IOP is a possible side effect associated with agents used to treat DME, especially steroids. Therefore, it is essential to duly inform and counsel patients on these possible side effects.
- In 98% to 99% of the cases, spike in IOP can be managed with topical antiglaucoma medication. The American Academy of Ophthalmology guidelines provide a list of antiglaucoma medications along with their respective potential to reduce IOP.14 Based on the extent of IOP reduction required, the patient can be treated individually with the “step up” approach where the target IOP and choice of antiglaucoma medication can be tailored accordingly. These IOP reduction rates are applicable only when used as a first drug, and IOP reduction rates would become much smaller when used as a second drug.
- Level 1 evidence shows that <1% of patients with IOP spike will require surgical intervention.15
- In patients diagnosed with ocular hypertension (OHT), any glaucoma including normal tension glaucoma, steroid response, their condition MUST be stable before proceeding with intravitreal steroid treatment and these patients MUST remain on their anti-glaucoma therapy throughout their intravitreal treatment regime.
- In patients with history of glaucoma or steroid response, intravitreal dexamethasone can be used safely under these circumstances:
- ∘ IOP Must be controlled before initiation of the treatment.
- ∘ Patients remain on antiglaucoma medication throughout steroid treatment regimen.
- ∘ Patients are followed-up closely (1 week and 2 weeks post-treatment) then at 6 weeks post-treatment.
- If IOP spike is detected, immediate treatment is recommended.
- Antiglaucoma medication from any class of drugs can be used as the first-choice monotherapy.
- ∘ If the drug provides good tolerability and is effective in reducing IOP, it should be continued till target IOP is reached. Periodically parameters such as visual field, IOP, optic disc, and quality of life should be verified.
- If the drug is not well tolerated or is not effective in reducing IOP, switch to another drug or introduce additional anti-glaucoma agents accordingly. If the IOP target is not reached, refer to a glaucoma specialist.
Recommendations for Cataract
Development of cataract is another side effect associated with intravitreal steroid treatment. Some of the recommendations pertaining to development of cataract are as follows:
- Cataract surgery is the best treatment for cataract to achieve maximum best-corrected visual acuity (BCVA).
- DME patients should be informed and counseled on the possible development of cataract between 12 and 24 months of treatment (after treatment with 2–4 injections), and if VA is affected, the management to achieve best final BCVA treatment is to have cataract surgery.
- Patients with preexisting cataract will have early worsening of their cataracts with intravitreal steroid treatment and will also require cataract surgery to achieve best final BCVA.
- In DME patients, who are undergoing cataract extraction, administration of intravitreal steroids (dexamethasone) can be considered at the time of cataract surgery. The consensus group recommended intravitreal steroid to be administered post-phacoemulsification after intraocular lens is implanted and wound is stable (ie, at the end of the cataract surgery).
DME has an intrinsic potential to cause vision loss and therefore warrants appropriate treatment. Before developing an individualized treatment plan for DME patients, it is essential to consider factors such as severity of the disease, risk for cataract, presence of exudates, history of vitrectomy, appropriate use of anti-VEGF and steroids, and patient compliance.
Classification of DME Patients Before Treatment Plan
Treatment plan is influenced by factors such as perfusion status (ischemic or non-ischemic), vitreomacular interface (presence of vitreomacular interface abnormality or not), location of edema (central involvement or noncentral involvement), clinical course (nonchronic or chronic), and distribution of the edema (focal or diffuse).16 The panellists were in agreement that classification of DME patients was necessary before planning individualized treatments for patients. It has been previously suggested that choice of treatment for DME should be based on the presence or absence of ischemic maculopathy.16 However, it has also been shown that the response of DME with or without significant ischemic maculopathy is almost identical between anti-VEGF and dexamethasone.17 With regards to performing fluorescein angiography at presentation or treatment failure, the panellists could not arrive at a consensus due to conflicting evidence for peripheral ischemia playing a role in persistent macular edema (Table 1). However, assessment of periphery using wide-field OCT angiography could expand the information further during the course of management.
Anti-VEGF Versus Steroids
Anti-VEGF agents are clinically effective in DME patients. However, evidence suggests that there is an inflammatory element in DME. Therefore, a significant proportion (>40%) of patients with DME may not respond to anti-VEGF treatment alone.6 In addition, there are differences in treatment volume between pivotal trials (9–12 injections per year) and real-world studies (3–4 injections; in some cases, 6–7 injections per year).18
Studies have shown that dexamethasone results in greater improvements in mean BCVA change from baseline in the pseudophakic patients than in phakic patients.19 In a recently published prospective study, intravitreal dexamethasone which was used as primary therapy (pro re nata) was found to be effective in early intervention of treatment-naive phakic eyes.20 A 2-year treatment with intravitreal dexamethasone (median number of injections: 1.6 per year) improved mean BCVA and median central subfield thickness. In addition, cataract developed only in 1.96% of the patients with a clear lens, and only one-fifth of the patients required topical antiglaucoma therapy. Although intravitreal bevacizumab and intravitreal dexamethasone provided comparable VA outcomes, intravitreal dexamethasone provided better anatomical outcomes than intravitreal bevacizumab over 12 months.21
Steroid implants have demonstrated good and safe clinical outcomes in treatment-naive patients.22 Early switching from anti-VEGF to steroids offers better treatment outcomes.23 The panellists were in agreement that treatment could be switched to alternative treatment such as other anti-VEGFs in the category or steroids if there was inadequate response after 3 anti-VEGF injections. In a retrospective study which investigated switching between various drugs for DME, intravitreal dexamethasone was found to provide better improvement compared with switching within the anti-VEGF class.24 Compared with other steroids, intravitreal dexamethasone is associated with slightly lesser systemic side effects.25 In countries where intravitreal dexamethasone is not readily available, the authors recommend use of intravitreal triamcinolone after evaluating the risk of side effects such as cataract progression and increase in intraocular pressure.
Targeting Inflammation in DME
Inflammation plays an important role in the pathogenesis of DME. In DME patients wherein inflammation is a major contributor in the pathogenesis, steroids may provide more effective treatment outcomes. Corticosteroids especially intravitreal dexamethasone targets not only VEGF, but also various inflammatory pathways of DME. This includes retinal leukostasis, and synthesis of proinflammatory mediators (interleukin 6, monocyte chemoattractant protein-1) which are significant in the pathogenesis of DME.26
Specific circulating proinflammatory cytokines as serum biomarkers and their possible correlation with the progression of DR and DME have been reported.27 VEGF plays a role in the production of DME, but it is not the only cytokine or only inflammatory factor. Severity of DR correlates with cytokine levels but not VEGF. Tumor necrosis factor-alpha levels have been associated with progression of DR, whereas interleukin-6 correlates with progression of DME. The panellists believe that despite the reports of inflammatory markers correlating with the progression of DR and DME, these markers are currently insufficient to determine the extent of inflammation in DR and DME, and therefore, do not play a role in defining treatment management.
Hard exudates are formed due to incomplete clearance of DME28 and can lead to severe central visual impairment.29 Since long-term results of surgical removal and macular laser have been poor,30,31 management approach focuses on preventing hard exudates from reaching foveal center. Intravitreal ranibizumab, intravitreal triamcinolone, and intravitreal dexamethasone have been effective in resolving hard exudates.32–34 Intravitreal dexamethasone has been shown to result in greater resorption of hard exudates from foveal center compared with intravitreal bevacizumab after 12 months.35
The use of intravitreal corticosteroids can accelerate cataract development.36 In phakic patients, intravitreal dexamethasone was associated with cataract-related adverse events in 67.9% of patients.13 Cataract development is also observed in anti–VEGF-treated patients; however, the incidence rate is lower [anti-VEGF (0–15%) versus Steroids (0–50%)].37 The panel has provided recommendations in managing patients with possible risk of cataract (see recommendation IV). Since vision loss from cataract can be reversed by cataract surgery, choosing the most effective treatment modality for each DME patients precedence over the risk of cataract progression; however, patients still require counseling for this complication. Due to its anti-inflammatory activity, steroid is the most preferred treatment post-cataract surgery. Cataract surgery and intravitreal dexamethasone injection can therefore be performed at the same time/setting.
Glaucoma and IOP Rise
Rise in IOP (>25 mm Hg) was observed with intravitreal dexamethasone in only one-fifth of the injected eyes over a mean follow-up period of 16.8 months for all indications.38 IOP-lowering medication was required for 31% of the eyes and only 3 eyes with preexisting glaucoma required filtering surgery. In the subgroup analysis, half of glaucoma patients who were previously treated with 2 medications and all patients who were previously treated with 3 medications at baseline had an increase of >15 mm Hg after the first intravitreal dexamethasone.
Anti-VEGF treatment can not only lead to spikes in IOP but also to persistent OHT that requires IOP-lowering treatment.39 The cumulative probability of sustained IOP elevation with anti-VEGF in 3 years was almost 10%.40 Overall, anti-VEGF agents can be used in DME patients with severe or uncontrolled glaucoma and in cases of OHT without glaucoma or glaucoma treated with monotherapy. Intravitreal dexamethasone can be used after a careful risk-benefit evaluation in stable glaucoma patients treated with monotherapy. A retrospective study by Srinivasan et al investigated the IOP changes after intravitreal dexamethasone implant in patients with glaucoma and steroid responders (815 patients).13 It was found that these patients had IOP spikes within 2 weeks (46.43% in 1st week, 39.00% in 2nd week) and 78.60% of patients with pressure rise were controlled with 1 topical antiglaucoma medication. No patient underwent surgical intervention. This study emphasizes that close follow-up is essential at week 1 and week 2 post-treatment to identify rising IOPs in glaucoma patients and modify treatment immediately. Based on the results of this study, post-treatment recommendations in DME patients treated with intravitreal dexamethasone were developed (Recommendations).
The effect of anti-VEGF is not well established in vitrectomized eyes. Some studies show a decrease in intravitreal efficacy due to increased clearance of the molecule,41 whereas another study shows no significant difference in BCVA and CMT between vitrectomized and nonvitrectomized eyes after anti-VEGF injections in patients with DME.42 Similar results have been observed with triamcinolone acetonide.43
Intravitreal dexamethasone implants are effective in treating persistent DME both in vitrectomized and nonvitrectomized eyes.44 Vitrectomy does not influence the efficacy and safety profile of dexamethasone implants for DME.45 Analysis of the currently available data and response profiles for the different molecules for DME supports the preferential use of intravitreal dexamethasone in vitrectomized eyes.
A retrospective study by Sudhalkar et al, on patients with at least 1 intravitreal dexamethasone implant injection, was carried out to determine the association between the dexamethasone implant position in the vitreous cavity and ocular hypertension.46 The study concluded that implants that remain in close proximity to the ciliary body/pars plana region (and the anterior segment) are associated with a higher probability of developing OHT and also more likely to require 3 drugs therapy for IOP control. It was also observed that patients who did not demonstrate a significant rise in IOP with the first injection did not demonstrate significant rise in IOP with the subsequent injections.
Cost and Compliance/Reimbursement Models
Cost of treatment is one of the important factors affecting therapeutic compliance in Asia. The reimbursement models play an important role in relieving the financial burden of the patients. The consensus panel attempted to capture the various reimbursement models in different Asian countries for the treatment of DME which is compiled in Table 4.
The recommendations were developed through a consensus method. Hence, the recommendations reflect the opinions of the participants. However, consensus was achieved with the reference of empirical evidence wherever necessary. The recommendations mainly focuses on therapeutic approach for DME with or without central involvement. Not all categories of DME are emphasized in the recommendations.
There are significant unmet needs in our current management of DME using anti-VEGF therapy. It has been shown that a significant proportion of patients with DME do not respond to anti-VEGF treatment. The high treatment burden leads to treatment fatigue, patient noncompliance, high societal cost, and suboptimal visual results from under-treatment. A large body of evidence supports the use of alternative treatments such as intravitreal dexamethasone, not just as second-line agent where response to anti-VEGF agents is poor, but also as first-line therapy in several conditions such as pseudophakic, poor-compliance, vitrectomized eyes, and patients undergoing cataract surgery. Steroids have a more significant anti-inflammatory effect compared with anti-VEGF, and therefore are useful in DME patients with high inflammatory component. Intravitreal dexamethasone reduces the treatment burden compared with other therapeutic regimens. The consensus guideline adequately addresses the precautions to be taken during steroid/intravitreal dexamethasone treatment due to its possible side effects such as IOP spike, glaucoma, and cataract progression. Based on these recent developments in the management of DME, the clinical guidelines in Asia require an update.
The authors wish to thank Dr. Leonard Yip, Glaucoma consultant, Tan Tok Seng Hospital, Singapore for his suggestions and input for the recommendations related to treating intraocular pressure spike and glaucoma. The authors also wish to thank Allergan for the educational grant and Dr. Hanusya Gunasagaran, Medical Affairs Manager of Asia Sub-Region, Allergan for supporting the consensus meeting and the development of this article. The authors acknowledge the editorial support provided by Mr. Vikram S Shenoy.
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