Saudi Journal of Ophthalmology (2010) 24, 143–149
`
`King Saud University
`
`Saudi Journal of Ophthalmology
`
`www.ksu.edu.sa
`www.sciencedirect.com
`
`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 management of DR, it remains a challenging
`condition to manage. The standard of care for patients with DR include strict metabolic control of
`hyperglycemia, blood pressure control, normalization of serum lipids, prompt retinal laser photo-
`coagulation and vitrectomy. For patients who respond poorly and who progressively lose vision in
`spite of the standard of care, intravitreal administration of steroids or/and anti-vascular endothelial
`growth factor (anti-VEGF) drugs appear to be a promising second-line of therapy. This review dis-
`cusses the current concepts and the role of these novel therapeutic approaches in the management of
`DR.
`
`ª 2010 King Saud University. All rights reserved.
`
`Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144
`1.
`2. Causes of visual loss in DR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144
`3.
`Standard of care in DR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
`4.
`Intravitreal drugs for managing DR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
`Intravitreal steroid injections (Silva et al., 2009) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146
`5.
`
`* 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 ª 2010 King Saud University. All rights reserved. Peer-
`review under responsibility of King Saud University.
`doi:10.1016/j.sjopt.2010.06.003
`
`Production and hosting by Elsevier
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`A. Pai et al.
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`Intravitreal steroids for DME . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146
`5.1.
`Intravitreal steroids for PDR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146
`5.2.
`6. Anti-VEGF therapy in DR (Neelakshi et al., 2009; Jardeleza and Miller, 2009) . . . . . . . . . . . . . . . . . . . . . . . . . . . 146
`6.1. Bevacizumab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147
`6.2. Ranibizumab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147
`6.3.
`Pegaptanib . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147
`6.4. VEGF Trap-eye . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147
`7. Combination therapy with intravitreal steroids and anti-VEGF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147
`8. Combination therapy with laser and intravitreal drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148
`9.
`Enzymatic vitreolysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148
`10. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148
`Disclosure. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148
`References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148
`
`1. Introduction
`
`There is an epidemic of diabetes mellitus (DM) worldwide
`(Scanlon, 2009). Prevalence of diabetic retinopathy (DR) is also
`rising accordingly. DR is the major threat to sight in the working
`age population in the developed world (Zimmet et 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; Zimmet et al., 2001).
`The extent of visual impairment in diabetic patients with
`DR can undeniably be decreased with systemic and ocular ther-
`apeutic intervention as shown by many clinical trials. For last
`few decades, retinal laser photocoagulation has led a revolution
`in the management of diabetic 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 of treat-
`ment for 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 DR with intravitre-
`al administration of drugs.
`
`2. Causes of visual loss in DR
`
`Though the diabetic retinopathy progresses through various
`stages, as shown in Fig. 1, the treatment of DR in a 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 of proliferative dia-
`betic retinopathy (PDR), is considered a major risk 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.
`
`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
`DME as either 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 lm of the centre of the macula,
`(b) hard exudates at or within 500 lm of the centre of the mac-
`ula if associated with thickening of the adjacent retina, (c) a
`
`Figure 1 Classification of diabetic retinopathy.
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`zone or zones of retinal thickening of at least one disc diameter
`in size part of which is within one disc diameter of the centre of
`macula (The Early Treatment of Diabetic Retinopathy Study
`Research Group, 1985).
`The CSME is further classified into focal or diffuse type
`depending on the pattern of the dye leakage on fluorescein angi-
`ography (FA) (Neelakshi et al., 2009). In focal CSME, focal
`leakage tends to occur from microaneurisms often with extra-
`vascular lipoproteins in circinate pattern around them; and well
`defined areas of fluorescein leakage from the microaneurisms
`are seen on the FA. These microaneurisms are thought to cause
`the retinal thickening. In contrast, the diffuse type of CSME re-
`sults from a generalized breakdown of the 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 of vision 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 how to 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).
`The first step in managing DR is 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 HbA1c 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;
`Matthews et al., 2004; Sheth et al., 2006). Hyperlipidemia has
`been linked to the presence of retinal hard exudates in patients
`with retinopathy and evidence suggests that lipid-lowering ther-
`apy may reduce hard exudates and microaneurisms (Sheth
`et al., 2006; Lyons et 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 of retinal lesions to more severe forms.
`Over last 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) and regression 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,
`remains the standard of care (The Early Treatment of Diabetic
`Retinopathy Study Research Group, 1985; Neelakshi et al.,
`2009).
`
`4. Intravitreal drugs for managing DR
`
`Some patients with PDR and DME continue to lose vision de-
`spite the prompt laser treatment. Progression of visual loss
`continues to occur in 5% of patients 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 with laser alone. These newer insights 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. Some of them include: peribulbar steroid
`injections,
`intravitreal steroid injections,
`injection of sus-
`tained-release steroid intravitreal
`implants and intravitreal
`
`Table 1
`
`Intravitreal drugs for DR.
`
`Steroids
`Triamcinolone acetonide
`Triamcinolone acetonide implant (I-vation)
`Flucinolone acetonide implant (Retisert)
`Dexamethasone implant (Posidurex)
`
`Anti-VEGFs
`Bevacizumab (Avastin)
`Ranibizumab (Lucentis)
`Pegaptanib (Macugen)
`VEGF Trap-eye
`
`Enzymes
`Hyaluronidase
`Plasmin
`Microplasmin
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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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`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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`A. Pai et al.
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`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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`erative diabetic retinopathy. Int. Ophthalmol. Clin. 49, 95–107.
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