What have we learnt about the management of diabetic macular edema in the antivascular endothelial...

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REVIEW

CURRENTOPINION What have we learnt about the management of

diabetic macular edema in the antivascularendothelial growth factor and corticosteroid era?

opyright © 2015 Wolters

1040-8738 Copyright � 2015 Wolte

Aniruddha Agarwal, Salman Sarwar, Yasir J. Sepah, and Quan D. Nguyen

Purpose of review

To summarize the outcomes of the use of antivascular endothelial growth factor (anti-VEGF) agents andcorticosteroids on the treatment paradigm for diabetic macular edema (DME).

Recent findings

Favorable efficacy data along with acceptable long-term safety results of anti-VEGF agents have made themthe standard first-line therapy in the management of DME. Level I evidence from large, multicenter clinicaltrials has established the beneficial role of anti-VEGF agents and intravitreal steroids. In addition, the roleof anti-VEGF agents in the treatment of diabetic retinopathy has also been recently recognized. However,concerns such as suboptimal response, VEGF resistance, and long-term effects on retinal layers andvasculature have also been highlighted recently.

Summary

The use of anti-VEGF agents and corticosteroids has revolutionized the management of DME. Despite theadvantages including ease of administration, low incidence of adverse events, and concomitantimprovement in retinopathy status, limitations of this therapeutic approach have been recognized. Thecurrent review will focus on the lessons learnt in the management of DME in the anti-VEGF and steroid era.

Keywords

antivascular endothelial growth factor, corticosteroids, diabetic macular edema, intravitreal injection, laserphotocoagulation, neovascularization, vascular endothelial growth factor

Ocular Imaging Research and Reading Center (OIRRC), Stanley M.Truhlsen Eye Institute, University of Nebraska Medical Center, Omaha,Nebraska, USA

Correspondence to Quan D. Nguyen, MD, MSc, University of NebraskaMedical Center, 985540 Nebraska Medical Center, Omaha, NE 68198-5540, USA. Tel: +1 402 559 4276; fax: +1 402 559 5514; e-mail:[email protected]

Curr Opin Ophthalmol 2015, 26:000–000

DOI:10.1097/ICU.0000000000000152

INTRODUCTION

The number of individuals with diabetes is likely tocross 400 million by the year 2030 worldwide [1].Approximately 1 in every 25 individuals aged40 years or older in the USA suffers from diabeticmacular edema (DME) in at least one eye, the preva-lence of which is higher among individuals withhigher grades of retinopathy [2

&

]. There is a largeunmet need in the management of DME, whichcontinues to remain the leading cause of visualloss in the working age group [2

&

,3].Vascular endothelial growth factor (VEGF)-

mediated angiogenic pathway plays a central rolein the manifestations of DME [4]. The breakdown ofblood–retinal barrier due to VEGF and inflamma-tory mediators results in the accumulation of fluidin the center of the macula, leading to visual loss.These pathways have been targeted using anti-VEGFagents and corticosteroids. Large, pivotal multicen-ter clinical trials using intravitreal anti-VEGF agentsand steroids have triggered a paradigm shift in the

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management of DME. Consequently, in the last fewyears, the treatment strategies of DME have evolvedfrom laser photocoagulation to local, intravitrealdelivery of therapeutic agents.

Data from a number of studies have establishedthe need for further research to evaluate newermolecular targets for the treatment of DME, movingbeyond the steroid and anti-VEGF era [5

&

]. Sub-optimal response to anti-VEGF agents in a signifi-cant subset of patients have led to the discovery ofmultiple pathways that may be involved in the

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KEY POINTS

� Anti-VEGF agents and steroids have revolutionized themanagement of diabetic macular edema withsignificantly improved functional and structuraloutcomes compared with laser therapy.

� The quality-of-life outcomes in patients with diabeticmacular edema are superior with the use of anti-VEGFagents; however, it comes at a much higher cost to thehealthcare system.

� Suboptimal response to anti-VEGF agents and steroidsprovide evidence of multifactorial cause of diabeticmacular edema and has paved the way for the searchof newer therapeutic targets.

� Lessons learnt from the past clinical trials and studiesevaluating the treatment strategies for diabetic macularedema are important considerations in the design offuture clinical trial protocols.

Retinal, vitreous and macular disorders

pathogenesis of DME. The objective of this article isto review the lessons learnt thus far in the manage-ment of DME in this era of anti-VEGF agentsand corticosteroids.

PARADIGM SHIFT IN THE MANAGEMENTOF DIABETIC MACULAR EDEMA

The Early Treatment Diabetic Retinopathy Study(ETDRS) established the role of laser in preventingup to 15 letters (ETDRS scale) loss of best-correctedvisual acuity (BCVA) with prompt therapy [6]. How-ever, since then, treatment with intravitreal injec-tions has gained popularity because of the ease ofdrug delivery in an outpatient setting and fewerlong-term adverse events. Addition of laser toanti-VEGF therapy has not shown additional benefitover long term [7

&&

]. Currently, both anti-VEGFagents and intravitreal steroids are preferred overlaser and approved by the US Food and Drug Admin-istration (US FDA) for the treatment of DME. Rani-bizumab (Lucentis) was approved for the treatmentof DME in August 2012, followed by Aflibercept(Eylea), which received approval in July 2014. Dexa-methasone implant, (Ozurdex) and fluocinoloneacetonide insert (Iluvien) were approved by USFDA in September 2014 for the treatment of DME.Iluvien has been approved for use in patients whohave been previously treated with corticosteroidsand did not have a significant rise of intraocularpressure.

The Ranibizumab for Edema of the mAcula inDiabetes-2 study was a pioneering phase II, rando-mized, multicenter trial comparing the change inBCVA between ranibizumab and laser therapy [8]. At

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2 years, following intent-to-treat analyses, the meanBCVA improvement was 7.7 letters (ranibizumabmonotherapy), 5.1 letters (laser group), and 6.8letters (combination group). Subsequently, furtherphase II/III trials such as Ranibizumab Monotherapyor Combined with Laser versus Laser Monotherapyfor Diabetic Macular Edema (RESTORE) [9

&

], Safetyand Efficacy of Ranibizumab in Diabetic MacularEdema (RESOLVE) [10], Ranibizumab Injection inSubjects With Clinically Significant Macular EdemaWith Center Involvement Secondary to DiabetesMellitus (RISE and RIDE) [11], and the DiabeticRetinopathy Clinical Research Network (DRCR.net)studies [7

&&

] conclusively established the beneficialeffects of ranibizumab versus laser for the treatmentof DME.

Similarly, in the Bevacizumab or Laser Therapyin the Management of Diabetic Macular Edema(BOLT) study, a 24-month trial, patients withDME were randomized to receive either 1.25 mgintravitreal bevacizumab or laser therapy [12]. At1 year, the bevacizumab group gained a median of 8letters compared with 0.5 letters lost by the lasergroup. A pilot study demonstrated the potentialtherapeutic role of VEGF Trap (aflibercept) inDME [13]. Subsequently, the DME And VEGF trap-Eye: INvestigation of Clinical Impact (DA VINCI)study compared aflibercept (VEGF-Trap) monother-apy with laser photocoagulation [14] and demon-strated that patients receiving aflibercept gained amean of 8.5–11.4 letters versus a 2.5-letter improve-ment in the laser group. The Intravitreal Afliberceptfor Diabetic Macular Edema (VIVID and VISTA)studies were two randomized, multicenter pivotaltrials that also compared aflibercept with lasertherapy. Approximately one-third patients inboth the studies gained at least 15 letters comparedwith one-tenth in the laser monotherapy arm(P<0.0001) [15].

Currently, three anti-VEGF agents provide themost favorable BCVA outcomes compared with anyother agent used in the treatment of DME. A directhead-to-head comparison by the DRCR.net ProtocolT will provide better insight into the comparativeefficacy of the three agents for DME [16].

Corticosteroids have received less attentioncompared with anti-VEGF agents because of theirpotential for causing cataracts and glaucoma.Retisert implant containing 0.59 mg fluocinoloneacetonide, though showing promise, has a very highrate of adverse events such as cataract and glaucomaleading to restriction of its use in DME [17]. How-ever, second-generation, sustained-release pre-parations of steroids have shown beneficial effectsin the recent clinical trials. The Fluocinolone Ace-tonide for Macular Edema (FAME) A and B studies

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Management of diabetic macular edema Agarwal et al.

[18&&

], evaluating fluocinolone acetonide (Iluvien)in patients with refractory DME, showed animprovement of at least 15 letters in 28.7% patientsreceiving the 0.2 mg/day insert. Refractory DME wasdefined as persistent DME despite one or moremacular laser treatments. The Macular Edema:Assessment of Implantable Dexamethasone inDiabetes (MEAD) study [19

&&

], evaluating dexa-methasone implant, demonstrated at least 15-letterimprovement in BCVA from baseline in 22.2%patients receiving the 0.7 mg implant.

During the last few years, studies have shownthat BCVA gains are superior with anti-VEGF agentscompared with intravitreal steroids [6,20]. However,we have also learnt that corticosteroids provide avery viable alternative to anti-VEGF agents in casesin which patients either do not respond to anti-VEGF therapy or prefer the mode of delivery ofcorticosteroids over monthly intravitreal injections.

EARLY INTERVENTION AND NEWERMETHODS OF PATIENT EVALUATION

With much improved structural and functional out-comes with therapy, criteria for patient recruitmentin the recent clinical trials have changed to includepatients with even better BCVA at baseline andlower retinal thicknesses compared with prior stud-ies. We have also learnt that changes in anatomymay precede the changes in physiological manifes-tations because of macular edema. This lack of cor-relation between visual acuity and retinal thicknesshas consequently influenced the design of newerclinical trials and many investigators have adoptedadditional noninvasive methods (such as micro-perimetry) for evaluating retinal function inpatients with DME [21

&

,22].

BEYOND MACULAR EDEMA: BENEFICIALROLE OF ANTIVASCULAR ENDOTHELIALGROWTH FACTOR AGENTS ANDSTEROIDS IN DIABETIC RETINOPATHY

Large randomized clinical trials examining theeffect of anti-VEGF agents and steroids in DME havenot only shown reduction in DME and improve-ment in vision, but also regression of retinopathyand reduced risk of progression with long-term use[23,24

&&

]. Improvement in the anatomical outcomessuch as reduction in the hard exudate area mayoccur following anti-VEGF therapy [25].

The DRCR.net study, comparing ranibizumab ortriamcinolone combined with laser to laser mono-therapy for DME, showed that, compared with lasermonotherapy, eyes treated with 0.5 mg intravitrealranibizumab with prompt or deferred laser had a

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reduced cumulative probability of retinopathyworsening at 3 years [26]. Regression in the severityof retinopathy was also seen in the ranibizumab-treated eyes in the RESTORE study [27]. Ranibizu-mab-treated groups showed ETDRS retinopathyseverity score improvement by at least 3 steps at3 years [27].

At 2 years, in the RISE and RIDE study, 37.2% ofpatients in the 0.3 mg ranibizumab and 35.9% in the0.5 mg ranibizumab showed improvement in theirretinopathy severity score by at least 2 steps on theETDRS severity scale compared with only 5.4% inthe sham group (P<0.001) [23,24

&&

]. Improvementsin the retinopathy severity level were maintained at3 years in the ranibizumab-treated eyes. Comparedwith sham, eyes treated with ranibizumab showed areduced risk of diabetic retinopathy worsening andhad a lower cumulative probability of developingproliferative disease [24

&&

]. Retrospective analysis offluorescein angiography from patients enrolled inRISE and RIDE studies also showed that comparedwith sham, ranibizumab-treated group had a higherpercentage of patients with no posterior retinalischemia at 2 years. This suggests a protective effectof ranibizumab on the development of retinal non-perfusion with VEGF blockade [28

&&

].In VIVID and VISTA study, aflibercept-treated

groups had a significantly greater proportion ofpatients demonstrating an at least �2-step improve-ment in the retinopathy severity score at 52 weekscompared with laser [15]. The finding reiterates theregression of underlying retinopathy by anti-VEGFagents in addition to their observed efficacy in DME.

The US FDA has granted priority review andbreakthrough therapy designation (BTD) to ranibi-zumab (Lucentis) for diabetic retinopathy afterGenentech filed supplemental Biologics LicenseApplication (sBLA) in August 2014 [29]. Aflibercept(Eylea) was granted a BTD status for diabetic retin-opathy in patients with DME in September 2014[30,31].

In a study evaluating 0.59 mg fluocinoloneacetonide implant (Retisert) for the treatment ofrefractory DME, high rate of retinopathy severityimprovement and lower rate of worsening wereobserved in eyes treated with the implant comparedwith the standard of care (laser or observation), up to3 years’ follow-up [17]. It is not clear whether theseeffects were from steroid-induced decreased expres-sion of VEGF or other anti-inflammatory mechan-isms or a combination of both. Studies evaluatingdexamethasone intravitreal implant (Ozurdex;MEAD study [19

&&

]) or fluocinolone acetonideinserts (Iluvien; FAME A and B [18

&&

]) for the treat-ment of DME have not published the efficacy data ofthese agents on retinopathy severity.


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QUALITY OF LIFE AMONG PATIENTS WITHDIABETIC MACULAR EDEMAIn addition to improvement in vision, positivechanges in the quality of life (QoL) of patients havebecome important goals for the treating ophthal-mologist [32]. DME can reduce the QoL of patientswith diabetes, especially in advanced stages, asmeasured by various psychometric scales [33]. Inthe past, laser therapy had an adverse effect onhealth-related QoL and treatment satisfaction inpatients with DME [34]. Compared with laser,anti-VEGF agents result in superior QoL outcomesamong patients [35

&

].Evaluation of QoL is now incorporated as a part

of study design in various clinical trials for DME[36

&

,37,38&

]. Treatment with monthly intravitrealinjections is associated with significant psychologi-cal burden and anxiety. A standardized VisualFunction Questionnaire (VFQ) has been developedby the National Eye Institute (NEI-VFQ-25) andsubsequently validated in order to assess the visual-related functional outcomes following treatmentfor DME [39,40]. Treatment with ranibizumab hasshown improvement in the vision-related, patient-reported functional outcomes in DME [38

&

,41].Such analyses of QoL indices have become

relevant in the management of DME and designingof study protocols testing novel agents. Withincreasing knowledge, data comparing QoL indicesfollowing treatment with various anti-VEGF agentsand intravitreal corticosteroids may soon becomeavailable.

INCREASED COST OF THERAPY ANDSTRATEGIES TO REDUCE TREATMENTBURDEN

Initial studies evaluating the role of anti-VEGFagents favored a monthly injection approach. How-ever, the monthly injections of anti-VEGF agentshave tremendously increased the treatment burdenof DME in the last few years. Cost–effectivenessanalysis has been recently shown to be of clinicalrelevance in patients with DME [42]. Using standardmethods for health technology assessments, theestimated cost of intravitreal ranibizumab 0.5 mg($2337) is much higher than bevacizumab(US$348) and laser photocoagulation (US$1093).Each office visit combined with ancillary diagnosticimaging such as optical coherence tomography(OCT) required as a part of anti-VEGF treatmentresults in an additional burden of approximatelyUS$491 per visit (using standardized models)[43

&&

,44]. Intravitreal ranibizumab is only cost-effec-tive for those who are willing to pay (WTP) at least$71 271 per Quality-Adjusted Life Years (QALY),



whereas bevacizumab is a cost-effective treatmentoption at $11 138 per QALY [43

&&

]. However, it isimportant to note that the above cost analysis hasbeen performed with 0.5 mg dose of ranibizumab.The FDA-approved dose of ranibizumab for DME is0.3 mg, which costs approximately US$1170 perinjection. Thus, this WTP and cost–effectivenessanalysis appears to be overinflated compared withthe current cost of ranibizumab. Availability ofdetailed analysis of the cost–effectiveness for intra-vitreal steroids is limited.

In order to decrease this treatment burden, thepresent-day research also focuses on alternate treat-ment approaches such as as-needed or treat-and-extent strategies. Currently, monthly injections(RISE and RIDE [11]), pro re nata (PRN) approach(RESOLVE [10]), and treat-and-extend (RETAIN [45])are the main strategies of treating DME with anti-VEGF agents. The PRN and treat-and-extend strat-egies are considered a more favorable comparedwith the monthly approach because of the reducedcost burden. The RETAIN study is a randomizedclinical trial comparing treat-and-extend with thePRN approach [45]. At month 24, treat-and-extendarm was noninferior to the PRN, with approximately40% fewer patient visits and lesser annual medicalcost. Sustained-release corticosteroid delivery devi-ces such as Iluvien and Ozurdex have been devel-oped with an aim to decrease the treatment costsand risks associated with frequent injections. Inorder to contain the costs, sustained-release drugdelivery devices appear to be more practical for achronic condition such as DME.

Although there is an ongoing debate regardingthe most appropriate treatment strategy for DME,cost–effectiveness of the therapy and insurancereimbursements have become important consider-ations in designing clinical trials.

VARIABILITY OF RESPONSE AND THECONCEPT OF PERSONALIZED MEDICINE

Ranibizumab showed a significant improvement(�3 lines visual acuity) in only 44.8% in the RISEstudy [11], whereas 55.2% patients receiving thesame therapy failed to show a similar response. Ithas been proposed that in addition to the environ-mental factors, genetic makeup of patients may playa role in such variability [46]. Genetic make-up,studied in genome-wide association studies, linkagestudies, candidate gene analysis and VEGF single-nucleotide polymorphisms, has provided the basisfor individual variations in treatment response [47

&

].Studies have shown the associations of increasingseverity of retinopathy and DME with pharmacoge-nomic markers such as human leucocyte antigen



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(HLA) DR-3, candidate gene alleles such as C667T inMTHFR gene and –634G/C (405 G/C) mutation inVEGF gene among several others. Polymorphismsin VEGF gene may alter its phenotypical expression,rendering it resistant to therapy. In the last fewyears, importance of information on comprehensivegene expression analyses of the patients enrolled invarious clinical trials for DME has been emphasized.Difference in gene expression can help identifyresponders and nonresponders to therapy [47

&

].Personalized medicine is a new concept that we

have learnt in the management of DME. The con-cept of ‘one-size-fits-all’ for the treatment of DMEhas been shed. Introduction of pharmacogenomicprinciples in the management of DME may allowtailored treatment based upon an individual’sgenetic profile in the future.

Currently, various clinical trials are beingdesigned to allow evaluation of genotype of theindividuals enrolled in the study. Assessment ofgene expression may help in expanding our know-ledge on genomic biomarkers for DME.

ROLE OF MULTIPLE PATHWAYS ANDFUTURE DIRECTIONS IN THEMANAGEMENT OF DIABETIC MACULAREDEMA

Pathological changes of DME are secondary tomultiple inflammatory and angiogenic pathways.This is evidenced by the suboptimal response toanti-VEGF agents and steroids in more than 50%patients with DME. Anti-VEGF agents block theintraocular downstream actions of VEGF. On theother hand, steroids block leukostasis and expres-sion of prostaglandins, cytokines and VEGF. Thishas led the investigators to determine the combinedefficacy of anti-VEGF agents and steroids in DME,but the results were not encouraging [48]. Thus, itcan be hypothesized that pathways other than theones inhibited by anti-VEGF agents and steroidsmay contribute to the development of DME. Assayof intraocular fluid from patients enrolled in trialsof DME for levels of various inflammatory markershas become an integral part of study design.

Better understanding of the pathophysiology ofDME and the therapeutic response to anti-VEGF andcorticosteroids has led to the development of newtherapeutic targets [49]. These include agents suchas antagonists of insulin-like growth factor (IGF-1)[50], inhibitor of vascular endothelial-proteintyrosine phosphatase (VE-PTP) that activates TIE-2(angiopoietin) receptor [51

&

], designated ankyrinrepeat proteins (DARPin) that bind to VEGF andhave a longer duration of action [52

&

], and vascularadhesion protein (VAP-1) inhibitor [53], to name a



few. These agents affect various cellular signalingpathways that may contribute to DME. For instance,TIE-2 is a receptor for angiopoietin family that playsa critical role in angiogenesis and retinal or choroi-dal neovascularization. TIE-2 is activated by anendothelial enzyme, VE-PTP, which increases withhypoxia. AKB-9778 (Aerpio Therapeutics, Cincin-nati, Ohio, USA) is a novel, small molecule thatinhibits the phosphatase activity of VE-PTP, result-ing in enhanced phosphorylation of TIE-2 anddownstream reduction of vascular permeability[54]. The treatment response of these novel agentsis being compared to ranibizumab as a standard oftherapy. Synergistic actions with ranibizumab arealso being evaluated as a part of these trials.

In addition to intravitreal drug delivery, efficacyof systemic administration of novel drugs for themanagement of DME is also being evaluated. This isbased on the premise that diabetes being a systemicdisease, various end-organ vascular complicationsincluding DME may be targeted simultaneously bynewer, experimental pharmacologic agents.

Newer laser photocoagulation techniques thatdeliver short pulses (micropulse) result in less ther-mal damage to the neural retina and choriocapilla-ries compared to the conventional laser used in theETDRS [55]. This subthreshold micropulse diodelaser may be capable of treating DME withoutdiscernible changes on fluorescein angiography orOCT. Laser-based treatment strategies appear to bepromising futuristic modalities for treating DME,either alone or in combination with anti-VEGFand steroids [56

&

].

CONCLUSION

During the last 5 years, treatment with anti-VEGFagents and corticosteroids has revolutionized andestablished a new standard of care in the manage-ment of DME. At the same time, the cost of treat-ment has risen exponentially. The biological effectsof anti-VEGF agents and steroids have providednewer insights into the multifactorial pathogenesisof DME. Anti-VEGF agents have become the first-line treatment option for DME, replacing laserphotocoagulation. The rapid reduction in DMEand significant visual acuity gain achieved by earlyinitiation of anti-VEGF therapy has raised thebenchmark for other potential therapeutic agentsfor DME. However, there are numerous challengeswith anti-VEGF and steroid therapy with significantproportion of patients showing suboptimalresponse and the need for frequent therapy. Thus,newer, longer acting agents with different thera-peutic targets, either as monotherapy or in combi-nation with anti-VEGF agents, are being evaluated



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in the USA and throughout the world and may besoon coming to the clinics in the poststeroid andanti-VEGF era.

Acknowledgements

None.

Financial support and sponsorship

This study was supported in part by an unrestricted grantfrom the Research to Prevent Blindness (RPB) to theTruhlsen Eye Institute at the University of NebraskaMedical Center.

Conflicts of interest

Q.D.N. serves on the Scientific Advisory Boards forGenentech, Inc., Bausch and Lomb, Inc., and Regeneron,Inc. The other authors have no conflicts of interest.

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