Saudi Journal of Ophthalmology (2010) 24, 143 149
`
`
`
`King Saud University
`
`Saudi Journal of Ophthalmology
`
`www.ksu.edu.sa
`www.sciencedirect.com
`
`
`
`gl) abel 4snd) SeenSAUD! OPHTHALMOLOGICAL SOCIETY
`
`
`
`
`
`REVIEW ARTICLE
`
`Current concepts in intravitreal drug therapy for
`diabetic retinopathy
`
`Anant Pai, MD, DNB, FRCS *, Maha M.El Shafei, MD, MS, FRCSI,
`Osman A.Z. Mohammed, MSc, FRCS(Ed), Mustafa Al Hashimi, MD
`
`Ophthalmology Section, Surgery Department, Hamad Medical Corporation, Doha, Qatar
`
`Received 5 June 2010; accepted 22 June 2010
`Available online 30 June 2010
`
`KEYWORDS
`Diabetic retinopathy;
`Intravitreal steroids;
`Anti VEGF drugs
`
`Contents
`
`Abstract Diabetic retinopathy (DR) is a major cause of preventable blindness in the developed
`countries. Despite the advances in understanding and managementof DR,it remains a challenging
`condition to manage. The standard of care for patients with DR includestrict metabolic control of
`hyperglycemia, blood pressure control, normalization of serum lipids, prompt retinal laser photo
`coagulation and vitrectomy. For patients who respond poorly and whoprogressively lose vision in
`spite of the standardofcare, intravitreal administration of steroids or/and anti vascular endothelial
`growth factor (anti VEGF) drugs appearto be a promising secondline of therapy. This review dis
`cusses the current concepts and therole of these novel therapeutic approaches in the management of
`DR.
`
`© 2010 King Saud University. All rights reserved.
`
`1.
`2.
`3.
`4.
`5.
`
`Introduction... 2...nec eee eee eee eee eee eens 144
`Causes of visual loss in DR...2. eee eee ee eee eee e eee 144
`Standard of care in DR...2...cn eee eee ee eee eee eee 145
`Intravitreal drugs for managing DR... 2... nee e eee eens 145
`Intravitreal steroid injections (Silva et al., 2009)... 2... eee eee eee eee 146
`
`* Corresponding author. Address: Ophthalmology Section, P.O. Box
`3050, Hamad Medical Corporation, Doha, Qatar. Tel.: +974 6514206.
`E mail address: anantgpai@hotmail.com (A.Pai).
`
`1319 4534 © 2010 King Saud University. All rights reserved. Peer
`review underresponsibility of King Saud University.
`doi: 10.1016/j.sjopt.2010.06.003
`
`ELSEVIER
`ae Productionandhosting by Ebevier
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`144
`
`A.Paiet al.
`
`5.1.
`146
`Intravitreal steroids for DME ... 2... eee ee eee eee eee
`5.2.
`Intravitreal steroids for PDR... 22.ee eee ee eee eee eens 146
`6. Anti VEGFtherapy in DR (Neelakshiet al., 2009; Jardeleza and Miller, 2009) ...............02..0.-00004.- 146
`6.1.
`Bevacizumab .. 2... 2...ee eee eee ee eee eee eee eee e eee 147
`6.2. Ranibizumab .. 2.2... ene eee e ee eee e eee eee eee 147
`6.3.
`Pegaptanib.. 2.2...ee ene ence eee eee eee e eee 147
`6.4. WEGF Trap eye .. 2...ne nent eee e ee ee eee eee eee 147
`7. Combination therapy with intravitreal steroids and anti VEGF... .. 2.2... 0... cee eee 147
`8. Combination therapy with laser and intravitreal drugs... 2.2... 2...ee eee eee 148
`9.
`Enzymatic vitreolysis.2...nee eee ee eee nett eee eee 148
`10. Conclusions .. 2...en eee eee eee eee eee eee eee eee eae 148
`Disclosure. 2...6 eee eee eee eee eee ee ee eee eee 148
`References 2...6.en ee eee eee ee eee eee eee eee eee eee eee 148
`
`The diabetic macular edema (DME) in the most common
`cause of moderate visual
`loss in patients with DM (Klein
`et al., 1984; Moss et al., 1988). DME may be associated with
`any of the stages of retinopathy. DME is defined as retinal
`thickening or presence of hard exudates within one disc diam
`eter of the centre of the macula (The Early Treatment of Dia
`betic Retinopathy Study Research Group, 1985; Klein et al.,
`1991, 1995; Neelakshi et al., 2009). The Early Treatment of
`Diabetic Retinopathy Study (ETDRS)
`further classified
`DMEaseither clinically significant macular edema (CSME)
`or non clinically significant, depending on its location and
`the presence of any associated exudates (Neelakshi et al.,
`2009; Wilkinson et al., 2003). DME becomes CSME if one
`or more of the following three conditions are present: (a) reti
`nal thickening at or within 500 pm of the centre of the macula,
`(b) hard exudates at or within 500 xm ofthe centre of the mac
`ula if associated with thickening of the adjacent retina, (c) a
`
`
`
`No clinical retinopathy
`
`Mild NPDR
`(Only microaneurisms)
`
`
`
`Moderate NPDR
`(More than microaneurisms, but less
`than severe NPDR)
`
` J S
`
`evere NPDR
`(More than 20 intraretinal haemorrhagesin each of 4
`quadrants, venous beading in 2 2 quadrants, IRMAin21
`
`qyadrant and nosigns of PDR)
`J
`
`
`PDR
`
`(New vessels elsewhere and/or around disc and/or
`preretinal / vitreous haemorrhages)
`
`Figure 1
`
`Classification of diabetic retinopathy.
`
`1. Introduction
`
`There is an epidemic of diabetes mellitus (DM) worldwide
`(Scanlon, 2009). Prevalence ofdiabetic retinopathy (DR)is also
`rising accordingly. DRis the major threat to sight in the working
`age population in the developed world (Zimmetet al., 2001).
`Furthermore, DR is increasing as a major cause of blindness
`in other parts of world including the eastern Mediterranean
`and middle eastern region representing an enormous public
`health problem (Scanlon, 2009; Zimmetet al., 2001).
`The extent of visual impairment in diabetic patients with
`DRcan undeniably be decreased with systemic and ocular ther
`apeutic intervention as shown by manyclinical trials. For last
`few decades,retinal laser photocoagulation hasled a revolution
`in the managementofdiabetic retinopathy. Just as dramatic as
`laser photocoagulation, advances in instrumentation and vit
`reo retinal surgical techniques have also been able to salvage vi
`sion in many patients with advanced stages of DR.
`Since the DR is a complex entity with multi factorial etiol
`ogy it needs multipronged approach to treatment. Though the
`laser photocoagulation has remained as the mainstay oftreat
`mentfor patients with DR,there is a distinct sub group of eyes
`with DR which do not respond adequately to laser photocoag
`ulation. This limitation has promoted interest to search for
`alternative treatment modalities. Several therapeutic modali
`ties are under investigation presently. This article will address
`the current concepts in the management of DRwith intravitre
`al administration of drugs.
`
`2. Causes of visual loss in DR
`
`Though the diabetic retinopathy progresses through various
`stages, as shownin Fig. 1, the treatment of DR ina patient de
`pends on the cause/s of visual loss. The two main causes of vi
`sual loss/impairment in patients with diabetic retinopathy are:
`proliferative diabetic retinopathy (PDR) and diabetic macular
`edema (DME).
`Retinal neovascularization, a hallmark ofproliferative dia
`betic retinopathy (PDR), is considered a majorrisk factor for
`severe vision loss in patients with DM (Abdulla and Fazwi,
`2009). PDR can be further categorized as early, high risk, or
`advanced, depending on the degree and severity of retinal
`new vessels, presence of vitreous or pre retinal hemorrhage
`and retinal detachment.
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`Current concepts in intravitreal drug therapy for diabetic retinopathy
`
`145
`
`zone or zonesofretinal thickening ofat least one disc diameter
`in size part of whichis within one disc diameter of the centre of
`macula (The Early Treatment of Diabetic Retinopathy Study
`Research Group, 1985).
`The CSMEis further classified into focal or diffuse type
`depending on the pattern ofthe dye leakage on fluorescein angi
`ography (FA) (Neelakshi et al., 2009). In focal CSME,focal
`leakage tends to occur from microaneurisms often with extra
`vascularlipoproteins in circinate pattern around them; and well
`defined areas of fluorescein leakage from the microaneurisms
`are seen on the FA. These microaneurismsare thought to cause
`the retinal thickening. In contrast, the diffuse type of CSME re
`sults from a generalized breakdown ofthe blood retinal barrier
`resulting into profuse leakage from the entire capillary bed in
`the posterior pole. The diffuse CSME is characterized by gen
`eralized intraretinal leakage from the retinal capillary bed
`and/or from intraretinal microvascular abnormalities (IRMAs)
`and/or from arterioles and venules (in severe cases), without
`any discrete areas of leakage from the microaneurisms. Hence
`diffuse CSME is more challenging to manage as compared to
`the focal type (Neelakshi et al., 2009).
`
`3. Standard of care in DR
`
`Several large, randomized, controlled clinical trials have pro
`vided the scientific basis for taking care ofvision in the diabetic
`patients with DR (The Early Treatment of Diabetic Retinopa
`thy Study Research Group, 1985; The Diabetes Control and
`Complications Trial Research Group, 1993; UK Prospective
`Diabetes Study (UKPDS) Group, 1998; The Diabetic Retinop
`athy Study Research Group, 1976, 1981, 1987; Early Treat
`ment Diabetic Retinopathy Study Research Group, 1991).
`The guidelines set forth by these landmark studies have re
`duced the incidence of visual impairment/loss by helping the
`clinician in determining when and howto treat the DR (The
`Early Treatment of Diabetic Retinopathy Study Research
`Group, 1985; The Diabetes Control and Complications Trial
`Research Group, 1993; UK Prospective Diabetes Study
`(UKPDS) Group, 1998; The Diabetic Retinopathy Study Re
`search Group, 1976, 1981, 1987; Early Treatment Diabetic
`Retinopathy Study Research Group, 1991).
`Thefirst step in managing DRis to control the underlying
`DM because prolonged hyperglycemia is a major risk factor
`for the development and progression of DR. Intensive meta
`bolic control, as reflected by the HbA,, level, not only reduces
`the mean risk of developing retinopathy but also lowers the
`risk of progression (The Diabetes Control and Complications
`Trial Research Group, 1993; UK Prospective Diabetes Study
`(UKPDS) Group, 1998). The available data also suggests that
`proper management of hypertension can reduce diabetes
`induced retinal complications (Funatsu and Yamashita, 2003;
`Matthewset al., 2004; Sheth et al., 2006). Hyperlipidemia has
`been linked to the presence ofretinal hard exudates in patients
`with retinopathy and evidence suggests thatlipid lowering ther
`apy may reduce hard exudates and microaneurisms (Sheth
`et al., 2006; Lyonset al., 2004; Miljanovic et al., 2004; Chew
`et al., 1996; Klein et al., 1991). It is important to appreciate that
`these treatments not only delay the onset of DR but also slow
`the progression ofretinal lesions to more severe forms.
`Overlast 2 3 decades, laser photocoagulation has remained
`as the mainstay and the standard of care for managing patients
`
`with sight threatening DR: both PDR and DME (The Early
`Treatment of Diabetic Retinopathy Study Research Group,
`1985; Neelakshi et al., 2009; The Diabetic Retinopathy Study
`Research Group, 1976, 1981, 1987). Panretinal photocoagula
`tion (PRP) with lasers is the standard practice of managing
`PDR (The Diabetic Retinopathy Study Research Group,
`1976, 1981, 1987). Laser photocoagulation reduces the oxygen
`demand of the outer layers of the retina and helps divert
`adequate oxygen and nutrients to the inner retinal
`layers,
`thus favorably altering the haemodynamics and introducing
`more choroidal oxygen to the ischemic inner retina, with a
`resultant reduction in hypoxia mediated secretion of vascular
`endothelial growth factor (VEGF) andregression of neovascu
`larization. In patients with DME too,the retinal laser photo
`coagulation in the form of focal laser for focal CSME or
`grid laser for diffuse CSME, as defined by the ETDRS,
`remainsthe standard of care (The Early Treatment of Diabetic
`Retinopathy Study Research Group, 1985; Neelakshi etal.,
`2009).
`
`4. Intravitreal drugs for managing DR
`
`Somepatients with PDR and DME continuetolose vision de
`spite the prompt laser treatment. Progression of visual loss
`continues to occur in 5% ofpatients in patients with PDR in
`spite of PRP (Aiello, 2005). In some patients of DME espe
`cially of diffuse CSME,the standard treatment with grid laser
`is somewhat
`less effective and more variable in outcome
`(Neelakshi et al., 2009). Thus, in day to day practice one com
`monly encounters some cases that are not/less responsive to
`the conventional laser therapy.
`Many theories have been proposed to explain the clinico
`pathological findings in PDR and DME,including biochemi
`cal, hemodynamic, endocrine, growth factors and inflamma
`tory theories. Hence, it may be inadequate to treat PDR and
`DME withlaser alone. These newerinsights into the pathogen
`esis of DR have improved our understanding of the disease
`and helped devise new treatment options with alternative or
`adjunctive pharmacologic therapies for those cases that are
`not responsive to thermal laser therapy.
`Different drugs and drug delivery systems are being tried in
`patients with DR. Someof them include: peribulbar steroid
`injections,
`intravitreal steroid injections,
`injection of sus
`tained release steroid intravitreal
`implants and intravitreal
`
`Intravitreal drugs for DR.
`
`Table 1
`Steroids
`Triamcinolone acetonide
`Triamcinolone acetonide implant (I vation)
`Flucinolone acetonide implant (Retisert)
`Dexamethasone implant (Posidurex)
`Anti VEGFs
`Bevacizumab (Avastin)
`Ranibizumab (Lucentis)
`Pegaptanib (Macugen)
`VEGFTrapeye
`
`Enzymes
`Hyaluronidase
`Plasmin
`
`Microplasmin
`
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`146
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`A. Pai et al.
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`administration of anti VEGF drugs. Most of them are being
`used as ‘‘off label’’ therapy. But some of them appear to be
`having more convincing roles in the management of DR espe
`cially in the patients with DME who are refractory to laser
`photocoagulation. All of these drugs (as shown in Table 1)
`are in different levels of clinical trials. Currently none of these
`medications have received approval from the Federal Drug
`Agency (FDA, USA) to treat DR.
`Given the roles of up regulated inflammatory mediators
`and vascular endothelial growth factors (VEGF) in the patho
`genesis of DR, intravitreal steroids and intravitreal anti VEGF
`therapy are commonly being used as second line therapy for
`patients with DR which are not responsive to laser therapy.
`Hence, we will discuss the roles of intravitreal steroids and
`intravitreal anti VEGF therapy in greater detail.
`
`5. Intravitreal steroid injections (Silva et al., 2009)
`
`The concept that DR is a low grade chronic inflammatory
`condition is gaining acceptance. Corticosteroids are potent
`anti inflammatory agents. In addition, they have been shown
`to inhibit the expression of VEGF, effectively reduce vascular
`permeability, prevent blood retinal barrier breakdown and in
`hibit certain matrix metalloproteinases. This broad biologic
`activity and multiple pharmacologic effects of corticosteroids
`support the rationale behind its use for treatment for DME
`and PDR.
`Among the corticosteroids being used in managing the DR,
`triamcinolone acetonide (TA) is more popular. TA can be
`administered by several routes, including intravitreal depot
`injection, periocular injection, posterior subtenon injection
`and intravitreal implant.
`
`5.1. Intravitreal steroids for DME
`
`Intravitreal administration of depot preparation of TA is an
`emerging therapy for persistent DME. Though it has been
`used in the dosages of 1 8 mg; the commonly used dosage is
`4 mg. The DME often improves after injection along with
`the visual acuity. Intravitreal TA has demonstrated short term
`efficacy for DME in multiple clinical trials. After depot injec
`tion, corticosteroid action peaks at 1 week, with residual activ
`ity persisting for 3 6 months. The two most common
`complications of intravitreal TA are cataract formation and
`raised intraocular pressure. The other less common complica
`tions reported with intravitreal TA injections are: endophthal
`mitis and rhegmatogenous retinal detachment. Peribulbar,
`rather than intravitreal, triamcinolone may reduce the risk of
`these adverse events. However, peribulbar triamcinolone ap
`pears to be less effective for DME than its intravitreal injection
`in multiple clinical trials.
`network
`Diabetic Retinopathy Clinical Research
`(DRCR.net) which conducted a randomized clinical multicen
`tric trial comparing intravitreal TA with macular laser treat
`ment reported that the visual acuity seemed to improve
`faster in the 4 mg TA group than in the laser group (Diabetic
`Retinopathy Clinical Research Network, 2008). But, the mean
`visual acuity and the reduction in the central retinal thickness,
`as measured by optical coherence tomography (OCT), at
`2 years after starting the treatment were better in the laser
`group compared to the TA group (Diabetic Retinopathy Clin
`
`ical Research Network, 2008). Cataract formation was more in
`4 mg TA group as compared to 1 mg TA group and laser
`group. This study indicated that focal/grid laser is a better
`treatment than TA in eyes with DME involving fovea with vi
`sual acuity between 20/40 and 20/320 (Diabetic Retinopathy
`Clinical Research Network, 2008).
`Intravitreal TA injection is a promising therapy for DME
`unresponsive to laser therapy. But, some patients require re
`injections as the therapeutic effect of TA diminishes after 3
`6 months. Repeated injections carry risk and are inconvenient
`to patients. To reduce the need for repeated intravitreal injec
`tions, a non biodegradable intravitreal implant, Retisert, has
`been developed for the extended release of flucinolone aceto
`nide within the posterior segment; and it is in phase 3 clinical
`trials. The other sustained release steroid implants being eval
`uated for DME are: dexamethasone implants (Posidurex,
`Allergan, CA, USA) and TA implant (I vation, Surmodics)
`both of which are in various levels of clinical trials.
`
`5.2. Intravitreal steroids for PDR
`
`PRP remains the current standard of care in the treatment of
`PDR. But, when PDR occurs concurrently with clinically sig
`nificant DME, management becomes more complex. As PRP
`has been reported to cause or worsen CSME, some prospective
`trials have been conducted to evaluate the role of combination
`of intravitreal triamcinolone with PRP in the management of
`PDR coexisting with CSME. Several small, clinical trials dem
`onstrated that the combination of laser photocoagulation
`(PRP laser and macular laser) with intravitreal TA was associ
`ated with improved visual acuity and decreased central macu
`lar thickness when compared with laser photocoagulation
`alone for the treatment of PDR and macular edema (Kang
`et al., 2006; Lam et al., 2007; Maia et al., 2009). Further
`studies are required to elucidate the role, long term efficacy
`and safety of intravitreal injection of steroids in patients with
`PDR.
`
`6. Anti-VEGF therapy in DR (Neelakshi et al., 2009; Jardeleza
`and Miller, 2009)
`
`In the patho physiologic cascade which leads to the DR,
`chronic hyperglycemia leads to ischemia which results in
`over expression of a number of growth factors, including vas
`cular endothelial growth factors (VEGF). Though blockade of
`all involved growth factors will likely be necessary to com
`pletely suppress the detrimental effects of ischemia, even iso
`lated blockade of VEGF may have beneficial effects in DR.
`VEGF is an endothelial cell specific angiogenic factor and
`it appears to play a major role in pathologic as opposed to
`physiologic, ocular neovascularization leading to PDR. VEGF
`is also a vasopermeable factor which increases vascular perme
`ability by relaxing endothelial cell junctions and this mecha
`nism is known to contribute to the development of DME.
`Inhibition of VEGF blocks these effects to some extent in
`DR, as demonstrated in several recent clinical trials and case
`series involving the anti VEGF molecules. Currently,
`the
`anti VEGF molecules which are commonly being studied in
`the management of DR are: pegaptanib (Macugen), rani
`bizumab (Lucentis), bevacizumab (Avastin) and VEGF
`Trap eye. Of the available VEGF antagonists, bevacizumab
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`Current concepts in intravitreal drug therapy for diabetic retinopathy
`
`147
`
`is the most frequently used outside of a formal clinical trial be
`cause it is less expensive.
`
`6.1. Bevacizumab
`
`Bevacizumab is a full length, recombinant, humanized anti
`body active against all isoforms of VEGF A. Several studies
`reported the use of the off label intravitreal injection of bev
`acizumab to treat DME and PDR. The commonly used typical
`dose is 1.25 mg, although doses as low as 6.2 lg and as high as
`2.5 mg have been used.
`Many studies have demonstrated beneficial effects follow
`ing intravitreal bevacizumab in patients with DME. Increased
`visual acuity with decrease in central retinal thickness with a
`single injection of bevacizumab lasts for 4 6 weeks. Hence re
`peated injections may be required for a prolonged effect. How
`ever, bevacizumab’s safety for intravitreal use for DR has not
`been tested in large, randomized studies.
`Intravitreal bevacizumab injection is an effective adjunct to
`conventional PRP in the treatment of PDR. Administering
`bevacizumab in conjunction with PRP for PDR results in
`greater and rapid regression of new vessels compared with
`PRP alone (Tonello et al., 2008; Mirshahi et al., 2008; Jorge
`et al., 2006). Bevacizumab also plays a role in the treatment
`of actively leaking new vessels refractory to adequately done
`laser in PDR. Some authors have studied the use of intravitreal
`bevacizumab in cases with dense vitreous hemorrhage that pre
`cludes the completion of PRP (Spaide and Fisher, 2006; Mora
`dian et al., 2008). This approach was suggested as an option
`for patients who refuse surgery or are unable to undergo sur
`gery due to their general condition (Abdulla and Fazwi,
`2009). Bevacizumab has also shown to prevent or lessen PRP
`associated macular edema. Moreover, bevacizumab can be
`very helpful in PDR complicated by neovascular glaucoma
`(Abdulla and Fazwi, 2009).
`Intravitreal bevacizumab injection a few days before the
`planned surgery facilitates surgical removal of fibrovascular
`membranes, reduces intra operative bleeding, reduces intra
`operative time, prevents re bleeding, and helps in accelerating
`post operative vitreous clear up (Ishikawa et al., 2009; Yeoh
`et al., 2008; Chen and Park, 2006; Rizzo et al., 2008). However,
`since, tractional retinal detachment may occur or progress
`shortly following the intravitreal bevacizumab, the surgery
`should be done within few days after its pre operative injection
`in these patients.
`Persistent and recurrent vitreous hemorrhage after vitrec
`tomy is a common complication associated with vitrectomy
`for diabetic retinopathy with an incidence ranging from 12%
`to 63% (Abdulla and Fazwi, 2009; Novak et al., 1984; Yang
`et al., 2008). Recurrent vitreous hemorrhage could delay visual
`rehabilitation and occasionally requires additional surgical
`procedures. It has been seen that the use of intravitreal bev
`acizumab at the end of surgery with or without supplementary
`endophotocoagulation reduces the incidence of re bleeding.
`
`6.2. Ranibizumab
`
`studies on intravitreal ranibizumab have demonstrated re
`duced foveal thickness and satisfactory visual outcome in pa
`tients with DME. Currently, READ 2 (Ranibizumab for
`Edema of the mAcula in Diabetes), a phase II study is ongoing
`in USA, to test the long term safety and effectiveness of intra
`ocular injections of ranibizumab in patients with DME.
`DRCR.net is also conducting randomized clinical trials to elu
`cidate the role of ranibizumab in patients with PDR.
`
`6.3. Pegaptanib
`
`Pegaptanib is an aptamer that binds the VEGF A 165 isoform.
`It differs from the above two anti VEGF drugs in that instead
`of targeting all active VEGF A isoforms,
`it prevents only
`VEGF 165 and larger isoforms from attaching to the VEGF
`receptors. Its intravitreal usage has shown good visual acuity
`outcomes, reduced central retinal thickness and reduced need
`for additional photocoagulation therapy in patients with
`DME. The retrospective analysis of the data of one study on
`patients who had concomitant DME and PDR at baseline,
`also demonstrated regression of new vessels after pegaptanib
`administration (Adamis et al., 2006).
`Given the potential systemic side effects of VEGF block
`ade, some authors advocate pegaptanib over bevacizumab
`and ranibizumab in DR, since pegaptanib selectively blocks
`VEGF 165, which plays essential role in pathological, but
`not physiological neovascularization. This is especially signifi
`cant in patients with DM since they may have co morbidities
`such as increased cardiovascular events, proteinuria and
`hypertension.
`
`6.4. VEGF Trap eye
`
`VEGF has two main receptors, VEGF receptor (VEGFR) 1
`and VEGR 2, which bind VEGF A, VEGF B, VEGF C,
`and placental growth factor (PGF) (Holash et al., 2002).
`VEGF Trap eye is a recombinant fusion protein consisting
`of the VEGF binding domains of VEGFR 1 and VEGFR 2
`fused to the Fc domain of human immunoglobulin G. VEGF
`Trap eye has a higher binding affinity for all VEGF A iso
`forms, about 140 times greater than ranibizumab (Nguyen
`et al., 2006). In addition, VEGF Trap eye maintains significant
`intravitreal VEGF binding activity for 10 12 weeks after a sin
`gle injection (Stewart and Rosenfeld, 2008). The theoretical
`advantages of VEGF Trap eye over ranibizumab include high
`er binding affinity, longer half life, and ability to inhibit other
`molecules such as PGF 1 and PGF 2 which may translate into
`clinical benefits of fewer intraocular injections and longer
`intervals between injections. Its single intravitreal
`injection
`has been found to be effective in patients with DME (Do
`et al., 2009).
`
`7. Combination therapy with intravitreal steroids and anti-
`VEGF
`
`Ranibizumab is a recombinant humanized antibody fragment
`that is active against all isoforms of VEGF A. The commonly
`used intravitreal dosage of ranibizumab is 0.5 mg. Its usage is
`also off label in DR in patients with DR. Like bevacizumab,
`ranibizumab is also being used for both DME and PDR. Some
`
`To enhance the therapeutic effects of intravitreally adminis
`tered steroids and anti VEGF drugs, it is logical to administer
`both of them together in the vitreous cavity in one sitting.
`Hence their intravitreal combination is also being tried in pa
`tients of DR who are refractory to conventional therapy.
`Intravitreal combination of TA and bevacizumab seems to
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`148
`
`A. Pai et al.
`
`be effective in improving visual acuity and reducing the macu
`lar thickness in patients with DME who are unresponsive to
`laser therapy (Tsilimbaris et al., 2009).
`
`8. Combination therapy with laser and intravitreal drugs
`
`Many clinical trials are underway presently to see whether com
`bination of laser with intravitreal drugs helps in any additional
`benefits in terms of efficacy and interval of treatments. Theoret
`ically, this combination provides hope of combining the short
`term benefit of intravitreal drug (e.g. decreased retinal thickness
`and decreased fluid leakage) and the long term benefit of laser
`photocoagulation (e.g.
`reduction in fluid leakage). The
`DRCR.net is conducting a phase III multicenter clinical trial
`to compare the efficacy of sham intravitreal injection with laser
`versus laser combined with 4 mg intravitreal triamcinolone ver
`sus laser combined with 0.5 mg intravitreal ranibizumab versus
`0.5 mg intravitreal ranibizumab with deferred laser.
`
`from DME and PDR. But, some patients may respond poorly
`and progressively lose vision in spite of this standard therapy.
`Newer insights into the biochemical changes and molecular
`events that occur with DM as well as with DR have led to no
`vel treatments which may be effective in patients when the
`standard care fails. The therapies which are currently being
`used more frequently when the response to the standard care
`is un satisfactory include intravitreal anti VEGF and cortico
`steroid based treatment strategies both of which form the sec
`ond line of therapy. Other new pharmacotherapies on the
`horizon also appear exciting at the moment. However, pro
`spective randomized clinical trials are needed to study the role
`of all these novel therapies.
`
`Disclosure
`
`None of the authors have any financial interests to disclose.
`Each author has equally contributed in the preparation of
`the manuscript.
`
`9. Enzymatic vitreolysis
`
`References
`
`The vitreous plays a role in the development of PDR and
`DME. The vitreous in diabetic patients undergoes structural
`modifications secondary to enzymatic and non enzymatic
`collagen glycation promoting collagen cross linking and vitre
`omacular traction; and this can worsen the DME. Further
`more, the retinal new vessels use the posterior hyaloid face
`as a scaffold to grow. The retracting vitreous pulls on these
`vessels and is responsible for both vitreous hemorrhage and
`retinal detachment in PDR. If this vitreous could be detached
`early and liquefied, the extent of the complications in PDR can
`be reduced. Hence, enzymatic vitreolysis and induction of pos
`terior vitreous detachment is being investigated as a minimally
`invasive non surgical treatment for DR.
`Vitreolysis, as a non surgical treatment in DR, has been
`suggested by using many potential enzymes like hyaluronidase
`(Kuppermann et al., 2005), plasmin and microplasmin intravit
`really. Hyaluronidase has been found to be non toxic; and ap
`pears to be effective in the clearance of vitreous hemorrhage
`and treatment of DR in Phase III clinical trials (Kuppermann
`et al., 2005).
`
`10. Conclusions
`
`Diabetic retinopathy, a devastating retinal manifestation of
`diabetes mellitus, is a serious global public health problem that
`diminishes the quality of life. The number of people worldwide
`who are at risk for developing vision loss from diabetes, is pre
`dicted to double over the next 25 years. Since DR can progress
`in the absence of symptoms, producing irreversible damage to
`the retina, regular screening examinations play a major role in
`reducing the magnitude of DR related visual impairment in the
`community.
`Once DR gets established, the evidence based therapies
`which form the standard of care for DR include strict meta
`bolic control of hyperglycemia, good blood pressure control,
`normalization of serum lipids, prompt retinal laser photocoag
`ulation and vitrectomy.
`Current techniques of improved laser photocoagulation
`and vitrectomy techniques will try in preserving the visual loss
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