New Treatments of Diabetic Retinopathy Arup Das 1,2, Steven Stroud 1, Aditya Mehta 1 and Sampathkumar Rangasamy 3 Department of Surgery/Ophthalmology, University of New Mexico School of
1
Medicine, Albuquerque, NM, USA New Mexico VA Heath Care System, Albuquerque, NM, USA
2
3
T‐Gen Institute, Phoenix, AZ, USA
Keywords: Diabetic retinopathy, diabetes complications, diabetes mellitus, blood‐ retinal barrier, VEGF Correspondence to: Arup Das, MD, PhD, Department of Surgery, Division of Ophthalmology, University of New Mexico School of Medicine, MSC10‐5610, 1 University of New Mexico, Albuquerque, NM 87131, USA E‐mail: [email protected]
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/dom.12384
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Abstract Diabetic retinopathy is the major cause of vision loss in middle‐aged adults. Alteration of the blood‐retinal barrier (BRB) is the hallmark of diabetic retinopathy, and later on hypoxia may result in retinal neovascularization. Tight control of systemic factors like blood glucose, blood pressure and blood lipids is essential in management of this disease. Vascular endothelial growth factor (VEGF) is one of the most important factors responsible for alteration of the BRB. Currently, the introduction of anti‐VEGF agents has revolutionized the therapeutic strategies in people with diabetic retinopathy, and the use of laser therapy has been somehow modified. In this article, we examine the clinical features and pathophysiology of the disease, and review the current status of new treatment recommendations for diabetic retinopathy, and also explore some possible future therapies. ABBREVIATIONS BRB = Blood‐retinal barrier; VEGF = Vascular endothelial Growth Factor; DME = Diabetic macular edema; PDR = Proliferative diabetic retinopathy; NPDR = Non‐ proliferative diabetic retinopathy; SDM Laser = Subthreshold Diode Micropulsar Laser; RPE = Retinal pigment epithelium; PRP = Panretinal photocoagulation; CSME = Clinically significant macular edema; DRCR = Diabetic Retinopathy Clinical Research network; TRD = Traction retinal detachment.
Introduction Diabetes mellitus is quickly becoming the global epidemic of the 21st century. Currently, there are 382 million people affected with diabetes mellitus in the world, and this number is projected to reach 592 million by 2035 [1]. The estimated global healthcare expenditures for treating diabetes and its complications were 376 billion US dollars in 2010, and this number is projected to exceed some 490 billion US dollars by 2030 [1]. Diabetic retinopathy, a microvascular complication of diabetes, is This article is protected by copyright. All rights reserved
prevalent in about 35% of people with diabetes [2]. It is the leading cause of vision loss in middle‐aged adults (20‐64 years) in developed countries [2, 3]. Although laser photocoagulation therapy has been the mainstay of management therapy in addition to control of systemic factors, the use of intravitreal anti‐vascular endothelial growth factor (VEGF) agents and steroids in recent years have revolutionized the management of diabetic macular edema. In this review, we will discuss the pathogenesis of diabetic retinopathy and the treatment strategies currently available for the treatment of diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR) (Table 1).
Clinical Features The earliest clinical lesions of diabetic retinopathy are microaneurysms, or focal dilations of retinal microvessels seen as deep red dots mainly in the posterior pole. Usually these lesions appear and disappear over time, and cause no symptoms themselves. Microaneurysms are present in almost all people with type 1 diabetes after 20 years duration of diabetes, and in 80 percent of people with type 2 diabetes [4, 5]. Based on the absence or presence of new vessels, diabetic retinopathy is classified into i) non‐proliferative (NPDR) and ii) proliferative diabetic retinopathy (PDR). Furthermore, NPDR is divided into four stages: mild, moderate, severe and very severe (Table 1). In the “mild‐moderate” stage, microaneurysms and intraretinal hemorrhages are present in the retina, mostly in the posterior pole. As the blood‐retinal barrier (BRB) breaks down, the plasma leaks out of the retinal capillaries resulting in retina edema. The edema most commonly occurs in the macula, resulting in distortion of vision and vision loss. Macular edema is the most common cause of vision loss in diabetic retinopathy (20‐25% of diabetics in 10 years). Hard exudates that look like well‐defined yellow deposits, often accompany macular edema, and these lesions represent lipid materials that leak out of the retinal microvessels. The NPDR becomes severe when it shows intraretinal hemorrhages in all four quadrants, or venous beading in 2 quadrants, or intraretinal microvascular This article is protected by copyright. All rights reserved
abnormalities (IRMA) in one quadrant (“4‐2‐1” rule) [6]. The retinopathy becomes “very severe” if two of these features are present. Fifty percent of the people with severe NPDR progress to the PDR stage in 1 year [6]. The proliferative diabetic retinopathy (PDR) is present when retinal new vessels grow out of the retinal capillaries into the vitreous. As these new vessels are fragile (endothelial tube), they often lead to preretinal and vitreous hemorrhage, causing symptoms of floaters and decreased, severe vision loss. As the new vessels grow over the vitreous interface, other cells like fibroblasts and glial cell participate in forming epiretinal membranes that contract and cause traction retinal detachment with severe vision loss. Some of the people with PDR show growth of the neovascular tissue on the surface of the iris into the anterior chamber angle, causing blockage of the aqueous outflow, and a severe type of glaucoma, called “neovascular glaucoma”.
Pathophysiology The alteration of the blood‐retinal barrier (BRB) is the hallmark of the pathogenesis of diabetic retinopathy. Normally, this BRB at the retinal capillary level comprises of endothelial cell‐cell junctions, basement membrane and pericytes that cover the vessels outside. In diabetes, three changes happen at the BRB: i) loss of endothelial cell‐cell junctions, ii) thickening of the basement membrane, and iii) selective loss of pericytes. The breakdown of the BRB leads to intraretinal hemorrhages, hard exudates and macular edema. Selective pericyte loss is one of the early histopathologic lesions seen in diabetic retinopathy [7]. It is not clear why there is selective loss of pericytes in diabetes. Normally, pericytes (modified smooth muscle cells), are contractile, and maintain the retinal capillary flow [8]. Pericyte loss leads to focal weakening of the capillary wall as well as uninhibited focal endothelial cell proliferation that leads to formation of microaneurysms [9]. Later, endothelial cells also die resulting in acellular capillaries, and non‐perfusion in the retina. Apoptosis or programmed cell death is responsible for death of both these cell types in diabetes. Neuronal death due to apoptosis may occur in the ganglion cell layer even This article is protected by copyright. All rights reserved
earlier than the vascular lesions. Such a silent death of neurons before the vascular lesions appear may explain the defect in dark adaptation and reduced contrast sensitivity seen in diabetic people before the development of retinopathy. The hyperglycemia‐induced pathogenesis of diabetic retinopathy is linked to four major biochemical pathways such as a) increased polyol pathway, b) increased AGE‐ product (advanced glycation end product) formation, c) activation of protein kinase C (PKC) isoforms, and d) increased hexosamine pathway (10). All these pathways eventually lead to oxidative stress, inflammation and retinal vascular dysfunction. Hypoxia is the initiating factor in the development of retinal new vessels seen in PDR. Many angiogenic factors like VEGF, bFGF, IGF, angiopoietin‐2 play a key role in this process [11]. Normally there is a balance of angiogenic factors and endogenous anti‐angiogenic factors (like PEDF, endostatin), and this balance breaks down in PDR, ultimately resulting in growth of new vessels.
Systemic Factor Control The beneficial effects of systemic control of blood glucose on retinopathy have been demonstrated in three large, randomized clinical trials. The Diabetes Control and Complications trial (DCCT) showed that tight glucose control (a glycated hemoglobin of less than 6% or 42.1 mmol/mol) in type 1 diabetics prevented development of diabetic retinopathy by 76% and a decreased progression of existing diabetic retinopathy by 54% [12]. The United Kingdom Prospective Diabetes Study (UKPDS) then revealed that intensive glucose control (median glycated hemoglobin of 7.0% or 53 mmol/mol vs. 7.9% or 62.8 mmol/mol in conventional group) led to a 25% reduced rate of microvascular disease, including retinopathy, in type 2 diabetics [13]. More recently, the ACCORD‐Eye study divulged that tight glucose control in type 2 diabetics (median glycated hemoglobin of 6.4% or 46.4 mmol/mol in the intensive group vs. 7.5% or 58.5 mmol/mol in conventional group) reduced progression of diabetic retinopathy by 35% over a 4‐year span [14]. However, a recent meta‐analysis of the recent clinical trials in people with type 2 diabetes This article is protected by copyright. All rights reserved
concluded that intensive control of blood glucose did not prevent need of photocoagulation, nor the development of severe vision loss (15). In regards to blood pressure control, the UKPDS found that controlling blood pressure also led to a significant decrease in visual loss [13]. Interestingly, the ACCORD‐Eye study showed that tight hypertension control did not significantly decrease the incidence of diabetic retinopathy [14]. These results point to the notion that maintaining systolic blood pressure under 150 mm Hg likely has a therapeutic threshold of around 130 mm Hg systolic pressure, lower than which likely has little effect on reducing visual loss in diabetic retinopathy. Interestingly, a newer study, Hypertension Intervention Nurse Telemedicine Study (HINTS), has shown that lowering systolic blood pressures by a mean of 8 mm Hg over an 18 month span led to decreased progression of diabetic retinopathy among mostly male veterans monitoring blood pressures at home and receiving nurse telemedicine behavioral and medical interventions [16]. Although control of blood pressure overall likely reduces the progression of diabetic retinopathy, it has been shown that treatment with specific agents may have additional benefits. For instance, candesartan vs. placebo led to a 25% decreased incidence of diabetic retinopathy in type 1 diabetics [17] and led to a 34% increased regression of diabetic retinopathy in type 2 diabetics with mild retinopathy [18]. In regards to lipid control, it appears that LDL (low density lipoprotein cholesterol) and TG (triglyceride) levels are directly related to incidence and severity of diabetic retinopathy, while the HDL level is indirectly related [19]. The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study showed that fenofibrate (200 mg/d) reduced the need for retinopathy laser treatment in type 2 diabetics [20]. This was further confirmed in the ACCORD‐Eye study that provided evidence that fenofibrate added to simvastatin therapy in type 2 diabetics slowed down the progression of diabetic retinopathy at 4 years [14]. Among other risk factors, anemia has been associated with progression of diabetic retinopathy (21). The ETDRS study showed an association between decrease in hematocrit and increase in incidence of high‐risk PDR. In type 2 diabetes, a strong This article is protected by copyright. All rights reserved
correlation was observed between diabetic retinopathy and obstructive sleep apnea (22). Pregnancy has been associated with rapid progression of diabetic retinopathy, and this has been attributed to high levels of estrogens as well as serum IGF‐1 (insulin‐like growth factor) in pregnancy (23).
In treatment of diabetic retinopathy, the ophthalmologist should be in close
consultation with the primary care physician regarding tight control of blood glucose, blood pressure and blood lipids. One should aim for achieving the HbA1C level at 7%, as further lowering of blood glucose may be difficult to achieve in long standing type 2 diabetics, and may cause increased cardiovascular events and mortality (14). Regarding control of retinopathy, one should also aim at achieving systolic blood pressure below 140 mm, and add fenofibrates to the statin therapy for optimal blood lipid control.
Laser therapy:
Diabetic Macular Edema: The Early Treatment Diabetic Retinopathy Study
(ETDRS) in 1985 showed that the use of small, light intensity laser burns to microaneurysms, and/or diffuse area of thickening in a grid pattern resulted in a 50% reduction in severe vision loss [24]. Proposed underlying mechanisms behind this approach involve increased intraocular oxygen tension, a decreased production of vasoactive cytokines, primarily VEGF, and increased phagocytosis by retinal pigment epithelial cells (RPE) and glial cells. Recently, it has been proposed that RPE cells at the margins of burns participate in their own recovery through the modulation of various cytokines via photoreceptors [25, 26]. Because of the efficacy of anti‐VEGF agents for DME, the current indication of focal/grid laser is now limited to those patients with non‐center involving DME. In recent years, treatment has shifted towards selectively applying subthermal intensity to RPE cells, while sparing the neurosensory retina, therefore, reducing iatrogenic side effects caused by functional loss of retinal tissue and deep burns that
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caused long term scarring and fibrosis. Two principles help achieve this goal. One, longer laser wavelengths are used, 647 nm krypton red and 810 nm diode lasers, in order to reduce burn intensity and avoid absorption to macular chromophores. Second, the development of micropulsar techniques, which increase the delay between pulses, reduces the size of retinal lesions by eliminating heat diffusion and lesion growth following treatment. In 2005, a pilot study of the Subthreshold Diode Micropulsar (SDM) Laser, which utilized the 810 nm diode laser in sub‐optimal intensity to all areas of macular thickening, demonstrated that SDM laser photocoagulation was comparable to previous laser treatments and without any adverse effects or evidence of iatrogenic retinal damage [27‐29]. Further studies showed similar effects. In 2009, a prospective randomized control trial comparing the efficacy of SDM laser photocoagulation with conventional argon green laser utilized in the modified Early Treatment Diabetic Retinopathy Study (mETDRS) protocol, demonstrated at 12 months that best corrected visual acuity (BCVA) remained unchanged in either treatment arm. However, laser scars were identified in only 13.9% of eyes treated with SDM, while laser scars were identified in 59% of eyes treated with conventional green laser [30]. Furthermore, in a study conducted in Japan, fundus autofluorescence (FAF), which utilizes fluorescence from the retina to indicate the health of RPE cells, was utilized in order to objectively evaluate morphological changes in 24 eyes treated with SDM laser photocoagulation for centrally involving CSME. At 1 year follow‐up, fundus autofluorescence remained unchanged from baseline values in the SDM laser photocoagulation treatment arm, thus indicating that there was no RPE cell damage [31]. The lack of damage to deeper retinal cell layers and long‐term scarring, as evidenced by these studies, helped to pave for the introduction of high density SDM lasers in an effort to improve clinical outcomes. The theory behind the high density approach sought to increase lateral spread of thermally stimulated RPE cells, thus delivering
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approximately 900 burns throughout the macula, but avoiding the fovea, and even involving normal appearing areas of the retina. This hypothesis was investigated by Lavinsky et al. and reported in 2011, which showed that high density SDM laser photocoagulation demonstrated a superior improvement in best corrected visual acuity (BCVA) and central macular thickness (CMT) in comparison with low density SDM laser and the conventional argon laser therapy [32]. Another newly developed mode of subthermal laser therapy involves creating a horse‐shoe shaped macular grid pattern using yellow 577 nm PASCAL (Semiautomated Patterned Scanning Laser), which allows the physician to deliver multiple spots of photocoagulation simultaneously in a preset pattern. The PASCAL employs either 20 ms or 10 ms burns localized to the outer retina without changes to adjacent RPE cells or inner neuroretina, similar to SDM [33, 34]. However, unlike the invisible nature of SDM, the burn from the PASCAL is able to be tracked 1 hour post treatment by FD‐OCT demonstrating localized defects at the junction of photoreceptor inner and outer segments (IS/OS) and apical RPE. At 12 months, the FD‐OCT shows a normal IS/OS layer with burns only localized to the uppermost RPE layer of the retina [23]. The use of the Yellow 577 nm laser also gives it the ability to be titrated to a certain power. A new navigated laser (NAVILAS) photocoagulator, a prototype of retinal eye‐tracking laser delivery system with integrated digital fundus imaging allows registered image overlay and laser stabilization on the retina and thus higher rate of accuracy in the treatment of diabetic retinopathy lesions (35). The CAVNAV Study (Combination of Anti‐VEGF and Navigational Laser in Diabetic Macular Edema), a 12 month prospective cohort study showed reduced number of anti‐VEGF injections and a higher proportion of injection‐free patients with the combination therapy of anti‐VEGF drugs and NAVILAS laser compared to the monotherapy of anti‐VEGF injections in DME (36). Proliferative Diabetic Retinopathy: The Diabetic Retinopathy Study (DRS) revealed that panretinal photocoagulation (PRP) reduced the risk of severe visual loss by
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approximately half over 5 years [37]. Furthermore, the preservation of vision from panretinal photocoagulation has been demonstrated in the ETDRS follow‐up study [38]. In this procedure, stronger intensity, large size burns (500 um) are placed in the mideperipheral retina in a 360 degree fashion in one or two sessions. The treatment does not aim at new vessels directly, and causes a regression of new vessels in about six weeks. The mechanism for new vessel regression is probably due to increased oxygen tension the remaining retina, and thus decreased production of angiogenic factors (like VEGF). PRP laser therapy has been established as a mainstay of treatment for PDR, but there are notable side effects that should be considered, including the worsening of pre‐existing macular edema, and impairment of peripheral retina function and night vision [39]. The reduction of these side effects with favorable clinical outcomes has been (and will likely continue to be) the focus of evolving therapies. The administration of PRP laser did not fundamentally change until the introduction of the PASCAL in recent years. The aim of this device was to shorten the procedure time of PRP laser and decrease patient pain by decreasing stimulation of the ciliary nerves in the choroid while providing the same therapeutic outcomes [40]. The PASCAL employs less duration of photocoagulation, but more power, which has indeed been shown to decrease patient pain with similar outcomes when compared to conventional PRP [41]. Recently, the PETER PAN study revealed that a lower power setting achieved similar results with less vision loss vs. standard PRP settings [42]. Additionally, it has been demonstrated that single session multi‐ spot PASCAL photocoagulation is as efficacious as multi‐session single‐spot photocoagulation, and resulted in no difference in adverse macular edema effects [43]. This finding has the potential to increase patient compliance and result in cost savings from reduced visits. The retina visualization technologies have also impacted the treatment options for PDR and potentially have the potential to make targeted retinal photocoagulation a viable treatment option. Conventionally a provider dilates a patient’s eyes and uses
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a slit‐lamp or indirect lens technique to visualize the retina during photocoagulation procedures. However, new technology, specifically the Optos camera, allows a provider to visualize the retina up to 200 internal degrees (sometimes without pupillary dilation), perform fluorescein angiography, and autofluorescence to map subthreshold laser burns on the retina. The PETER PAN study also concluded that targeted retinal photocoagulation could be used in conjunction with visible peripheral retinal ischemia on Optos angiography [42]. The Optos device has a favorable safety profile and will likely continue to become more prominent in the treatment of retinopathy [44].
Pharmacotherapies: 1. Anti‐ VEGF Therapy: Vascular endothelial growth factor (VEGF) has been the most important factor that has been investigated extensively in relation to the pathophysiology retinal neovascularization and alteration of the BRB. The VEGF levels are significantly elevated in vitreous of patients with DME when compared with non‐diabetic eye conditions [45]. VEGF is a potent vaso‐permeability factor. It affects endothelial tight junction proteins, resulting in extravasation of fluid and retinal edema. VEGF induces the phosphorylation of VE‐cadherin, occludin, and ZO‐1, and thus causes a breakdown of the barrier [46]. VEGF also increases leukostasis in the retinal microvessels, and the sticky leukocytes may migrate via interendothelial or the transendothelial route [47]. There are several drugs that target the molecule, VEGF. Drugs that directly inhibit the VEGF molecule include the anti‐VEGF aptamer, pegaptanib (Macugen, OSI), the monoclonal antibody fragment Ranibizumab (Lucentis, Genentech), and the full length antibody bevacizumab (Avastin, Genentech). Other treatment modalities include soluble VEGF receptor analogs,
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VEGF‐Trap (Regeneron), small interfering RNAs (siRNAs) bevasiranib (Opko Health), and rapamycin (Sirolimus, MacuSight). Anti‐VEGF drugs are injected into the eye in the form of intravitreal injections under topical anesthesia as office procedures. Currently, the indication for use of anti‐VEGF agents in DME is center‐ involving DME, where the indication of laser is limited to non‐center involving DME. Diabetic Macular Edema: Ranibizumab is a monoclonal antibody that blocks all isoforms of VEGF‐A, and is “affinity‐enhanced” to provide stronger affinity to bind to VEGF‐A. It is the only drug that has been approved by the US FDA for use in DME patients (Figure 1). The READ‐2 Study compared focal/grid laser treatment with intravitreal injection of ranibizumab only as well as a combination therapy of ranibizumab plus focal/grid laser. Three‐year results of the study showed mean improvement of visual acuity from the baseline as 10.3 letters compared to ‐1.6 letters in the laser group and +2.0 letters in the combination therapy group [48]. Two more studies also showed the beneficial effects of intravitreal ranibizumab injections in DME patients. In the RIDE/RISE study, where patients were randomized to either two different doses of intravitreal ranibizumab (0.3 mg and 0.5 mg) or sham injection, the proportion of patients showing >15 letter improvement were 19% in the sham group compared to 37% in the 0.3 mg ranibizumab group and 40% in the 0.5 mg ranibizumab group after 36 months [49]. Interestingly, this study demonstrated a beneficial effect of ranibizumab in slowing down the progression of diabetic retinopathy and improvement of the severity of retinopathy. The Diabetic Retinopathy Clinical Research Network (DRCR), a NIH sponsored multicenter, randomized clinical trial concluded that intravitreal ranibizumab with prompt or deferred laser was more effective through at least 1 year compared with prompt laser alone for center‐involving DME [50]. Three‐year data from this study indicated that visual improvement was more in the ranibizumab + deferred laser group (57% with >10 letters improvement) compared to the ranibizumab + prompt laser group
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(42% with >10 letters improvement), and thus suggested no benefit of earlier initiation of focal/grid laser for better visual outcome [51]. Although the first line of treatment of center‐involving DME is currently anti‐VEGF injections, the focal/grid laser therapy can be added to this anti‐VEGF regimen if the edema persists and is no longer improving for two consecutive injections after an initial period of 24 weeks of monthly anti‐VEGF injections (52). Bevacizumab (Avastin, Genentech) is a full‐length humanized monoclonal antibody, almost three times the size of the ranibizumab molecule, which also blocks all isoforms of VEGF‐A. It has been used as an “off‐label” drug for the treatment of age‐ related macular degeneration, retinal vascular occlusions, PDR and DME. Because of its much lower cost compared to other available drugs like ranibizumab and aflibercept, bevacizumb has gained world‐wide popularity in the eye clinics for treatment of retinal vascular diseases. The BOLT study that compared intravitreal injections of bavacizumab (1.25 mg, 6 weekly) with focal/grid laser treatment for 12 months showed an improvement of 8 letters with bevacizumab injections, whereas the laser group lost a median of 0.5 letters [53]. Two‐year results of this study demonstrated a similar improvement with bevacizumab. Aflibercept (Eylea, Regeneron) is a soluble protein that contains extracellular VEGF receptor sequences fused to an IgG molecule, and blocks all isoforms of VEGF as well as the placental growth factor. The prolonged biological activity of this drug offers the advantage of every‐other‐month injections rather than more frequent monthly injections. In the phase 3 VIVID‐DME and VISTA‐DME trials, patients receiving aflibercept (2 mg monthly or every other month) had a mean BCVA change from baseline of 12.5 and 11.1 letters, respectively, after two years compared to a mean change from baseline in BCVA of 0 .2 letters in patients receiving laser photocoagulation [54]. Currently, the DRCR is evaluating protocol T, a head‐to‐head comparison of the efficacy and safety of these three drugs, ranibizumab, bevacizumab and aflibercept in treatment of patients with diabetic macular edema
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[55]. Until we have the results published from this pivotal study, the ophthalmologists are left with their personal choice of anti‐VEGF drugs in DME patients. Also, there remains a large disconnect between what the randomized clinical trials publish and what the ophthalmologists actually do in their clinical practice in terms of the number of intravitreal injections. It is still a personal choice, regarding which drug to choose and how frequently to inject after the initial three monthly injections. Proliferative Diabetic Retinopathy: Anti‐VEGF therapy has been found to be very effective in rapid regression of retinal neovascularization seen in PDR patients [56]. However, the effects of anti‐VEGF agents appear to be transient, and therefore panretinal laser photocoagulation may still be necessary to allow for more permanent regression of new vessels. One needs to be cautious in using anti‐VEGF agents in those PDR patients with significant fibrovascular proliferation as these agents may worsen traction retinal detachment. Currently, a phase 3 prospective clinical trial is comparing prompt panretinal laser photocoagulation with intravitreal ranibizumab and deferred panretinal laser in PDR patients [57]. 2. Steroids: Inflammation plays an important role in the pathogenesis of diabetic retinopathy [58]. All the features of inflammation: increased blood flow, increased vascular permeability, tissue edema, leukostasis, microglial activation, macrophages and neutrophil infiltration, complement activation and increased cytokines (VEGF, TNFa, IL) have been reported in animal models as well as human diabetic retinopathy [59]. The inflammatory cytokines are upregulated in the serum, vitreous and aqueous samples in subjects with diabetic retinopathy. Inflammation can alter the BRB by acting on these steps in the cascade: (1) Increased expression of endothelial adhesion molecules such as ICAM1, VCAM1, PECAM‐1, and P‐selectin, (2) adhesion of leukocytes to the endothelium (leukostasis), (3) release of
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chemokines, and cytokines, (4) alteration of adherens and tight junctional proteins between the endothelial cells, and (5) infiltration of leukocytes into the neuro‐retina, resulting in the alteration of the blood retinal barrier [58]. Diabetic Macular Edema: The beneficial effects of steroids in DME are due to the fact that inflammatory cytokines and chemokines involved in the inflammatory cascade of DME are susceptible to steroids, whereas inhibition of VEGF itself may not result in neutralization of these molecules (Figure 2). The efficacy of intravitreal steroids in DME has been shown in the DRCR Protocol I. In this trial, the effect of intravitreal triamcinolone and laser was equivalent to that of ranibizumab and laser up to 24 weeks, and then the effect of triamcinolone gradually diminished because of increased rates of cataract formation [50]. In the subgroup of pseudophakic patients, the triamcinolone plus laser group was superior to the laser alone treatment and equivalent to the ranibizumab group [50]. In another randomized, multicenter three‐year long trial, the FAME study, intravitreal inserts of fluocinolone acetonide (0.2 ug/d and 0.5 ug/d) provided substantial benefit of visual improvement in patients with DME [59]. However, almost all patients receiving fluocinolone acetonide had cataract formation, and the incidence of incisional glaucoma surgery was 4.8% (low dose) and 8.1% (high dose). Although the US FDA did not approve this drug for DME because of its side effects, it has been recently approved in UK. It is interesting to note that the FAME study showed enhanced benefits of using fluocinolone acetonide in chronic DME (> 3 years duration) compared to nonchronic DME ( 5 letters in 56% of eyes receiving triamcinolon e vs. 26% of eyes receiving placebo58
b (0.5mg inj) improved visual acuity by >15 letters in 45.7% patients vs. 12.3% patients treated with sham injection37
13
Central Retinal Thickness
Fenofibrat e decreases progressio n of macular edema by 34% compared to placebo18
SDM equally as effective as conventional green laser (OCT measured central retina thickness of 255 vs. 248.9 um respectively) with less scarring55 Pascal laser equally as effective in treating CSME vs. conventional laser (28/30 vs. 27/30) 53 Pascal laser reduced FD-OCT by 20+/- 21 um at 3 months24 SDM and Pascal (double-frequency neodymium YAG laser 532 nm) have equally efficacy in reducing DME54
Intravitreal triamcinolon e injections are superior to posterior sub-tenon capsule injections in reducing foveal thickness59 Intravitreal triamcinolon e injections decreased macular thickness by a mean of 125 micrometers as compared to a mean decrease of 71 micrometers by placebo58
Ranibizuma b (0.5mg inj) decreased macular edema by 270.7 micrometer s compared to a decrease of 125.8 micrometer s in sham groups37 Ranibizuma b injections decreases foveal thickness less than laser therapy in DME36 44 patients receiving Ranibizuma b (0.5mg inj) received macular laser treatments vs. 94 patients in sham group37
Ranibizumab plus focal/grid laser reduced foveal thickness more than focal/grid laser alone in DME38,60
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Figure 1. Optical coherence tomography images of the study eye retina of a diabetic macular edema patient at baseline and months 1, 3 and 6. The patient received 0.3 mg of ranibizumab (Reproduced with permission from Chun et al Ophthalmology 2006; 113:1706‐1712).
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Figure 2. Pathophysiology and current strategies of therapies in diabetic macular edema (DME). Systemic factor control targeting blood glucose, blood pressure and lipids is still the gold standard treatment for diabetic retinopathy. Focal/grid laser is now indicated in those with non‐center involving DME only. Anti‐VEGF intravitreal injections are the first line of treatment in patients with center‐involving DME. Steroids are reserved for those who are poor responders to anti‐VEGF therapies. Finally, a small number of patients with vitreo‐macular traction are treated with vitrectomy surgery. Other potential novel target molecules are Ang‐2, CCL2, TNF‐α and IL‐1β. VEGF = vascular endothelial growth factor; Ang‐2 = angiopoietin 2; CCL2 = chemokine ligand 2; TNF‐α = tumor necrosis factor; IL‐1β = interleukin. DIABETES
Systemic Factor Control
Polyol, AGE, PKC & Hexosamine Pathway Activation
Hyperlipidemia
ROS INFLAMMATION Hypertension Growth Factors (VEGF), Chemokines & Cytokines (Ang-2, CCL2, TNF-α, IL-1β )
Anti-VEGF Therapies (for center-involving DME) Steroids
Altered Blood-Retinal Barrier
Increased vascular permeability
Focal/Grid LASER (for non-center involving DME)
Diabetic Macular Edema
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Vitrectomy
(for Vitreo-macular traction)
1
Medicine, Albuquerque, NM, USA New Mexico VA Heath Care System, Albuquerque, NM, USA
2
3
T‐Gen Institute, Phoenix, AZ, USA
Keywords: Diabetic retinopathy, diabetes complications, diabetes mellitus, blood‐ retinal barrier, VEGF Correspondence to: Arup Das, MD, PhD, Department of Surgery, Division of Ophthalmology, University of New Mexico School of Medicine, MSC10‐5610, 1 University of New Mexico, Albuquerque, NM 87131, USA E‐mail: [email protected]
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/dom.12384
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Abstract Diabetic retinopathy is the major cause of vision loss in middle‐aged adults. Alteration of the blood‐retinal barrier (BRB) is the hallmark of diabetic retinopathy, and later on hypoxia may result in retinal neovascularization. Tight control of systemic factors like blood glucose, blood pressure and blood lipids is essential in management of this disease. Vascular endothelial growth factor (VEGF) is one of the most important factors responsible for alteration of the BRB. Currently, the introduction of anti‐VEGF agents has revolutionized the therapeutic strategies in people with diabetic retinopathy, and the use of laser therapy has been somehow modified. In this article, we examine the clinical features and pathophysiology of the disease, and review the current status of new treatment recommendations for diabetic retinopathy, and also explore some possible future therapies. ABBREVIATIONS BRB = Blood‐retinal barrier; VEGF = Vascular endothelial Growth Factor; DME = Diabetic macular edema; PDR = Proliferative diabetic retinopathy; NPDR = Non‐ proliferative diabetic retinopathy; SDM Laser = Subthreshold Diode Micropulsar Laser; RPE = Retinal pigment epithelium; PRP = Panretinal photocoagulation; CSME = Clinically significant macular edema; DRCR = Diabetic Retinopathy Clinical Research network; TRD = Traction retinal detachment.
Introduction Diabetes mellitus is quickly becoming the global epidemic of the 21st century. Currently, there are 382 million people affected with diabetes mellitus in the world, and this number is projected to reach 592 million by 2035 [1]. The estimated global healthcare expenditures for treating diabetes and its complications were 376 billion US dollars in 2010, and this number is projected to exceed some 490 billion US dollars by 2030 [1]. Diabetic retinopathy, a microvascular complication of diabetes, is This article is protected by copyright. All rights reserved
prevalent in about 35% of people with diabetes [2]. It is the leading cause of vision loss in middle‐aged adults (20‐64 years) in developed countries [2, 3]. Although laser photocoagulation therapy has been the mainstay of management therapy in addition to control of systemic factors, the use of intravitreal anti‐vascular endothelial growth factor (VEGF) agents and steroids in recent years have revolutionized the management of diabetic macular edema. In this review, we will discuss the pathogenesis of diabetic retinopathy and the treatment strategies currently available for the treatment of diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR) (Table 1).
Clinical Features The earliest clinical lesions of diabetic retinopathy are microaneurysms, or focal dilations of retinal microvessels seen as deep red dots mainly in the posterior pole. Usually these lesions appear and disappear over time, and cause no symptoms themselves. Microaneurysms are present in almost all people with type 1 diabetes after 20 years duration of diabetes, and in 80 percent of people with type 2 diabetes [4, 5]. Based on the absence or presence of new vessels, diabetic retinopathy is classified into i) non‐proliferative (NPDR) and ii) proliferative diabetic retinopathy (PDR). Furthermore, NPDR is divided into four stages: mild, moderate, severe and very severe (Table 1). In the “mild‐moderate” stage, microaneurysms and intraretinal hemorrhages are present in the retina, mostly in the posterior pole. As the blood‐retinal barrier (BRB) breaks down, the plasma leaks out of the retinal capillaries resulting in retina edema. The edema most commonly occurs in the macula, resulting in distortion of vision and vision loss. Macular edema is the most common cause of vision loss in diabetic retinopathy (20‐25% of diabetics in 10 years). Hard exudates that look like well‐defined yellow deposits, often accompany macular edema, and these lesions represent lipid materials that leak out of the retinal microvessels. The NPDR becomes severe when it shows intraretinal hemorrhages in all four quadrants, or venous beading in 2 quadrants, or intraretinal microvascular This article is protected by copyright. All rights reserved
abnormalities (IRMA) in one quadrant (“4‐2‐1” rule) [6]. The retinopathy becomes “very severe” if two of these features are present. Fifty percent of the people with severe NPDR progress to the PDR stage in 1 year [6]. The proliferative diabetic retinopathy (PDR) is present when retinal new vessels grow out of the retinal capillaries into the vitreous. As these new vessels are fragile (endothelial tube), they often lead to preretinal and vitreous hemorrhage, causing symptoms of floaters and decreased, severe vision loss. As the new vessels grow over the vitreous interface, other cells like fibroblasts and glial cell participate in forming epiretinal membranes that contract and cause traction retinal detachment with severe vision loss. Some of the people with PDR show growth of the neovascular tissue on the surface of the iris into the anterior chamber angle, causing blockage of the aqueous outflow, and a severe type of glaucoma, called “neovascular glaucoma”.
Pathophysiology The alteration of the blood‐retinal barrier (BRB) is the hallmark of the pathogenesis of diabetic retinopathy. Normally, this BRB at the retinal capillary level comprises of endothelial cell‐cell junctions, basement membrane and pericytes that cover the vessels outside. In diabetes, three changes happen at the BRB: i) loss of endothelial cell‐cell junctions, ii) thickening of the basement membrane, and iii) selective loss of pericytes. The breakdown of the BRB leads to intraretinal hemorrhages, hard exudates and macular edema. Selective pericyte loss is one of the early histopathologic lesions seen in diabetic retinopathy [7]. It is not clear why there is selective loss of pericytes in diabetes. Normally, pericytes (modified smooth muscle cells), are contractile, and maintain the retinal capillary flow [8]. Pericyte loss leads to focal weakening of the capillary wall as well as uninhibited focal endothelial cell proliferation that leads to formation of microaneurysms [9]. Later, endothelial cells also die resulting in acellular capillaries, and non‐perfusion in the retina. Apoptosis or programmed cell death is responsible for death of both these cell types in diabetes. Neuronal death due to apoptosis may occur in the ganglion cell layer even This article is protected by copyright. All rights reserved
earlier than the vascular lesions. Such a silent death of neurons before the vascular lesions appear may explain the defect in dark adaptation and reduced contrast sensitivity seen in diabetic people before the development of retinopathy. The hyperglycemia‐induced pathogenesis of diabetic retinopathy is linked to four major biochemical pathways such as a) increased polyol pathway, b) increased AGE‐ product (advanced glycation end product) formation, c) activation of protein kinase C (PKC) isoforms, and d) increased hexosamine pathway (10). All these pathways eventually lead to oxidative stress, inflammation and retinal vascular dysfunction. Hypoxia is the initiating factor in the development of retinal new vessels seen in PDR. Many angiogenic factors like VEGF, bFGF, IGF, angiopoietin‐2 play a key role in this process [11]. Normally there is a balance of angiogenic factors and endogenous anti‐angiogenic factors (like PEDF, endostatin), and this balance breaks down in PDR, ultimately resulting in growth of new vessels.
Systemic Factor Control The beneficial effects of systemic control of blood glucose on retinopathy have been demonstrated in three large, randomized clinical trials. The Diabetes Control and Complications trial (DCCT) showed that tight glucose control (a glycated hemoglobin of less than 6% or 42.1 mmol/mol) in type 1 diabetics prevented development of diabetic retinopathy by 76% and a decreased progression of existing diabetic retinopathy by 54% [12]. The United Kingdom Prospective Diabetes Study (UKPDS) then revealed that intensive glucose control (median glycated hemoglobin of 7.0% or 53 mmol/mol vs. 7.9% or 62.8 mmol/mol in conventional group) led to a 25% reduced rate of microvascular disease, including retinopathy, in type 2 diabetics [13]. More recently, the ACCORD‐Eye study divulged that tight glucose control in type 2 diabetics (median glycated hemoglobin of 6.4% or 46.4 mmol/mol in the intensive group vs. 7.5% or 58.5 mmol/mol in conventional group) reduced progression of diabetic retinopathy by 35% over a 4‐year span [14]. However, a recent meta‐analysis of the recent clinical trials in people with type 2 diabetes This article is protected by copyright. All rights reserved
concluded that intensive control of blood glucose did not prevent need of photocoagulation, nor the development of severe vision loss (15). In regards to blood pressure control, the UKPDS found that controlling blood pressure also led to a significant decrease in visual loss [13]. Interestingly, the ACCORD‐Eye study showed that tight hypertension control did not significantly decrease the incidence of diabetic retinopathy [14]. These results point to the notion that maintaining systolic blood pressure under 150 mm Hg likely has a therapeutic threshold of around 130 mm Hg systolic pressure, lower than which likely has little effect on reducing visual loss in diabetic retinopathy. Interestingly, a newer study, Hypertension Intervention Nurse Telemedicine Study (HINTS), has shown that lowering systolic blood pressures by a mean of 8 mm Hg over an 18 month span led to decreased progression of diabetic retinopathy among mostly male veterans monitoring blood pressures at home and receiving nurse telemedicine behavioral and medical interventions [16]. Although control of blood pressure overall likely reduces the progression of diabetic retinopathy, it has been shown that treatment with specific agents may have additional benefits. For instance, candesartan vs. placebo led to a 25% decreased incidence of diabetic retinopathy in type 1 diabetics [17] and led to a 34% increased regression of diabetic retinopathy in type 2 diabetics with mild retinopathy [18]. In regards to lipid control, it appears that LDL (low density lipoprotein cholesterol) and TG (triglyceride) levels are directly related to incidence and severity of diabetic retinopathy, while the HDL level is indirectly related [19]. The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study showed that fenofibrate (200 mg/d) reduced the need for retinopathy laser treatment in type 2 diabetics [20]. This was further confirmed in the ACCORD‐Eye study that provided evidence that fenofibrate added to simvastatin therapy in type 2 diabetics slowed down the progression of diabetic retinopathy at 4 years [14]. Among other risk factors, anemia has been associated with progression of diabetic retinopathy (21). The ETDRS study showed an association between decrease in hematocrit and increase in incidence of high‐risk PDR. In type 2 diabetes, a strong This article is protected by copyright. All rights reserved
correlation was observed between diabetic retinopathy and obstructive sleep apnea (22). Pregnancy has been associated with rapid progression of diabetic retinopathy, and this has been attributed to high levels of estrogens as well as serum IGF‐1 (insulin‐like growth factor) in pregnancy (23).
In treatment of diabetic retinopathy, the ophthalmologist should be in close
consultation with the primary care physician regarding tight control of blood glucose, blood pressure and blood lipids. One should aim for achieving the HbA1C level at 7%, as further lowering of blood glucose may be difficult to achieve in long standing type 2 diabetics, and may cause increased cardiovascular events and mortality (14). Regarding control of retinopathy, one should also aim at achieving systolic blood pressure below 140 mm, and add fenofibrates to the statin therapy for optimal blood lipid control.
Laser therapy:
Diabetic Macular Edema: The Early Treatment Diabetic Retinopathy Study
(ETDRS) in 1985 showed that the use of small, light intensity laser burns to microaneurysms, and/or diffuse area of thickening in a grid pattern resulted in a 50% reduction in severe vision loss [24]. Proposed underlying mechanisms behind this approach involve increased intraocular oxygen tension, a decreased production of vasoactive cytokines, primarily VEGF, and increased phagocytosis by retinal pigment epithelial cells (RPE) and glial cells. Recently, it has been proposed that RPE cells at the margins of burns participate in their own recovery through the modulation of various cytokines via photoreceptors [25, 26]. Because of the efficacy of anti‐VEGF agents for DME, the current indication of focal/grid laser is now limited to those patients with non‐center involving DME. In recent years, treatment has shifted towards selectively applying subthermal intensity to RPE cells, while sparing the neurosensory retina, therefore, reducing iatrogenic side effects caused by functional loss of retinal tissue and deep burns that
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caused long term scarring and fibrosis. Two principles help achieve this goal. One, longer laser wavelengths are used, 647 nm krypton red and 810 nm diode lasers, in order to reduce burn intensity and avoid absorption to macular chromophores. Second, the development of micropulsar techniques, which increase the delay between pulses, reduces the size of retinal lesions by eliminating heat diffusion and lesion growth following treatment. In 2005, a pilot study of the Subthreshold Diode Micropulsar (SDM) Laser, which utilized the 810 nm diode laser in sub‐optimal intensity to all areas of macular thickening, demonstrated that SDM laser photocoagulation was comparable to previous laser treatments and without any adverse effects or evidence of iatrogenic retinal damage [27‐29]. Further studies showed similar effects. In 2009, a prospective randomized control trial comparing the efficacy of SDM laser photocoagulation with conventional argon green laser utilized in the modified Early Treatment Diabetic Retinopathy Study (mETDRS) protocol, demonstrated at 12 months that best corrected visual acuity (BCVA) remained unchanged in either treatment arm. However, laser scars were identified in only 13.9% of eyes treated with SDM, while laser scars were identified in 59% of eyes treated with conventional green laser [30]. Furthermore, in a study conducted in Japan, fundus autofluorescence (FAF), which utilizes fluorescence from the retina to indicate the health of RPE cells, was utilized in order to objectively evaluate morphological changes in 24 eyes treated with SDM laser photocoagulation for centrally involving CSME. At 1 year follow‐up, fundus autofluorescence remained unchanged from baseline values in the SDM laser photocoagulation treatment arm, thus indicating that there was no RPE cell damage [31]. The lack of damage to deeper retinal cell layers and long‐term scarring, as evidenced by these studies, helped to pave for the introduction of high density SDM lasers in an effort to improve clinical outcomes. The theory behind the high density approach sought to increase lateral spread of thermally stimulated RPE cells, thus delivering
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approximately 900 burns throughout the macula, but avoiding the fovea, and even involving normal appearing areas of the retina. This hypothesis was investigated by Lavinsky et al. and reported in 2011, which showed that high density SDM laser photocoagulation demonstrated a superior improvement in best corrected visual acuity (BCVA) and central macular thickness (CMT) in comparison with low density SDM laser and the conventional argon laser therapy [32]. Another newly developed mode of subthermal laser therapy involves creating a horse‐shoe shaped macular grid pattern using yellow 577 nm PASCAL (Semiautomated Patterned Scanning Laser), which allows the physician to deliver multiple spots of photocoagulation simultaneously in a preset pattern. The PASCAL employs either 20 ms or 10 ms burns localized to the outer retina without changes to adjacent RPE cells or inner neuroretina, similar to SDM [33, 34]. However, unlike the invisible nature of SDM, the burn from the PASCAL is able to be tracked 1 hour post treatment by FD‐OCT demonstrating localized defects at the junction of photoreceptor inner and outer segments (IS/OS) and apical RPE. At 12 months, the FD‐OCT shows a normal IS/OS layer with burns only localized to the uppermost RPE layer of the retina [23]. The use of the Yellow 577 nm laser also gives it the ability to be titrated to a certain power. A new navigated laser (NAVILAS) photocoagulator, a prototype of retinal eye‐tracking laser delivery system with integrated digital fundus imaging allows registered image overlay and laser stabilization on the retina and thus higher rate of accuracy in the treatment of diabetic retinopathy lesions (35). The CAVNAV Study (Combination of Anti‐VEGF and Navigational Laser in Diabetic Macular Edema), a 12 month prospective cohort study showed reduced number of anti‐VEGF injections and a higher proportion of injection‐free patients with the combination therapy of anti‐VEGF drugs and NAVILAS laser compared to the monotherapy of anti‐VEGF injections in DME (36). Proliferative Diabetic Retinopathy: The Diabetic Retinopathy Study (DRS) revealed that panretinal photocoagulation (PRP) reduced the risk of severe visual loss by
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approximately half over 5 years [37]. Furthermore, the preservation of vision from panretinal photocoagulation has been demonstrated in the ETDRS follow‐up study [38]. In this procedure, stronger intensity, large size burns (500 um) are placed in the mideperipheral retina in a 360 degree fashion in one or two sessions. The treatment does not aim at new vessels directly, and causes a regression of new vessels in about six weeks. The mechanism for new vessel regression is probably due to increased oxygen tension the remaining retina, and thus decreased production of angiogenic factors (like VEGF). PRP laser therapy has been established as a mainstay of treatment for PDR, but there are notable side effects that should be considered, including the worsening of pre‐existing macular edema, and impairment of peripheral retina function and night vision [39]. The reduction of these side effects with favorable clinical outcomes has been (and will likely continue to be) the focus of evolving therapies. The administration of PRP laser did not fundamentally change until the introduction of the PASCAL in recent years. The aim of this device was to shorten the procedure time of PRP laser and decrease patient pain by decreasing stimulation of the ciliary nerves in the choroid while providing the same therapeutic outcomes [40]. The PASCAL employs less duration of photocoagulation, but more power, which has indeed been shown to decrease patient pain with similar outcomes when compared to conventional PRP [41]. Recently, the PETER PAN study revealed that a lower power setting achieved similar results with less vision loss vs. standard PRP settings [42]. Additionally, it has been demonstrated that single session multi‐ spot PASCAL photocoagulation is as efficacious as multi‐session single‐spot photocoagulation, and resulted in no difference in adverse macular edema effects [43]. This finding has the potential to increase patient compliance and result in cost savings from reduced visits. The retina visualization technologies have also impacted the treatment options for PDR and potentially have the potential to make targeted retinal photocoagulation a viable treatment option. Conventionally a provider dilates a patient’s eyes and uses
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a slit‐lamp or indirect lens technique to visualize the retina during photocoagulation procedures. However, new technology, specifically the Optos camera, allows a provider to visualize the retina up to 200 internal degrees (sometimes without pupillary dilation), perform fluorescein angiography, and autofluorescence to map subthreshold laser burns on the retina. The PETER PAN study also concluded that targeted retinal photocoagulation could be used in conjunction with visible peripheral retinal ischemia on Optos angiography [42]. The Optos device has a favorable safety profile and will likely continue to become more prominent in the treatment of retinopathy [44].
Pharmacotherapies: 1. Anti‐ VEGF Therapy: Vascular endothelial growth factor (VEGF) has been the most important factor that has been investigated extensively in relation to the pathophysiology retinal neovascularization and alteration of the BRB. The VEGF levels are significantly elevated in vitreous of patients with DME when compared with non‐diabetic eye conditions [45]. VEGF is a potent vaso‐permeability factor. It affects endothelial tight junction proteins, resulting in extravasation of fluid and retinal edema. VEGF induces the phosphorylation of VE‐cadherin, occludin, and ZO‐1, and thus causes a breakdown of the barrier [46]. VEGF also increases leukostasis in the retinal microvessels, and the sticky leukocytes may migrate via interendothelial or the transendothelial route [47]. There are several drugs that target the molecule, VEGF. Drugs that directly inhibit the VEGF molecule include the anti‐VEGF aptamer, pegaptanib (Macugen, OSI), the monoclonal antibody fragment Ranibizumab (Lucentis, Genentech), and the full length antibody bevacizumab (Avastin, Genentech). Other treatment modalities include soluble VEGF receptor analogs,
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VEGF‐Trap (Regeneron), small interfering RNAs (siRNAs) bevasiranib (Opko Health), and rapamycin (Sirolimus, MacuSight). Anti‐VEGF drugs are injected into the eye in the form of intravitreal injections under topical anesthesia as office procedures. Currently, the indication for use of anti‐VEGF agents in DME is center‐ involving DME, where the indication of laser is limited to non‐center involving DME. Diabetic Macular Edema: Ranibizumab is a monoclonal antibody that blocks all isoforms of VEGF‐A, and is “affinity‐enhanced” to provide stronger affinity to bind to VEGF‐A. It is the only drug that has been approved by the US FDA for use in DME patients (Figure 1). The READ‐2 Study compared focal/grid laser treatment with intravitreal injection of ranibizumab only as well as a combination therapy of ranibizumab plus focal/grid laser. Three‐year results of the study showed mean improvement of visual acuity from the baseline as 10.3 letters compared to ‐1.6 letters in the laser group and +2.0 letters in the combination therapy group [48]. Two more studies also showed the beneficial effects of intravitreal ranibizumab injections in DME patients. In the RIDE/RISE study, where patients were randomized to either two different doses of intravitreal ranibizumab (0.3 mg and 0.5 mg) or sham injection, the proportion of patients showing >15 letter improvement were 19% in the sham group compared to 37% in the 0.3 mg ranibizumab group and 40% in the 0.5 mg ranibizumab group after 36 months [49]. Interestingly, this study demonstrated a beneficial effect of ranibizumab in slowing down the progression of diabetic retinopathy and improvement of the severity of retinopathy. The Diabetic Retinopathy Clinical Research Network (DRCR), a NIH sponsored multicenter, randomized clinical trial concluded that intravitreal ranibizumab with prompt or deferred laser was more effective through at least 1 year compared with prompt laser alone for center‐involving DME [50]. Three‐year data from this study indicated that visual improvement was more in the ranibizumab + deferred laser group (57% with >10 letters improvement) compared to the ranibizumab + prompt laser group
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(42% with >10 letters improvement), and thus suggested no benefit of earlier initiation of focal/grid laser for better visual outcome [51]. Although the first line of treatment of center‐involving DME is currently anti‐VEGF injections, the focal/grid laser therapy can be added to this anti‐VEGF regimen if the edema persists and is no longer improving for two consecutive injections after an initial period of 24 weeks of monthly anti‐VEGF injections (52). Bevacizumab (Avastin, Genentech) is a full‐length humanized monoclonal antibody, almost three times the size of the ranibizumab molecule, which also blocks all isoforms of VEGF‐A. It has been used as an “off‐label” drug for the treatment of age‐ related macular degeneration, retinal vascular occlusions, PDR and DME. Because of its much lower cost compared to other available drugs like ranibizumab and aflibercept, bevacizumb has gained world‐wide popularity in the eye clinics for treatment of retinal vascular diseases. The BOLT study that compared intravitreal injections of bavacizumab (1.25 mg, 6 weekly) with focal/grid laser treatment for 12 months showed an improvement of 8 letters with bevacizumab injections, whereas the laser group lost a median of 0.5 letters [53]. Two‐year results of this study demonstrated a similar improvement with bevacizumab. Aflibercept (Eylea, Regeneron) is a soluble protein that contains extracellular VEGF receptor sequences fused to an IgG molecule, and blocks all isoforms of VEGF as well as the placental growth factor. The prolonged biological activity of this drug offers the advantage of every‐other‐month injections rather than more frequent monthly injections. In the phase 3 VIVID‐DME and VISTA‐DME trials, patients receiving aflibercept (2 mg monthly or every other month) had a mean BCVA change from baseline of 12.5 and 11.1 letters, respectively, after two years compared to a mean change from baseline in BCVA of 0 .2 letters in patients receiving laser photocoagulation [54]. Currently, the DRCR is evaluating protocol T, a head‐to‐head comparison of the efficacy and safety of these three drugs, ranibizumab, bevacizumab and aflibercept in treatment of patients with diabetic macular edema
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[55]. Until we have the results published from this pivotal study, the ophthalmologists are left with their personal choice of anti‐VEGF drugs in DME patients. Also, there remains a large disconnect between what the randomized clinical trials publish and what the ophthalmologists actually do in their clinical practice in terms of the number of intravitreal injections. It is still a personal choice, regarding which drug to choose and how frequently to inject after the initial three monthly injections. Proliferative Diabetic Retinopathy: Anti‐VEGF therapy has been found to be very effective in rapid regression of retinal neovascularization seen in PDR patients [56]. However, the effects of anti‐VEGF agents appear to be transient, and therefore panretinal laser photocoagulation may still be necessary to allow for more permanent regression of new vessels. One needs to be cautious in using anti‐VEGF agents in those PDR patients with significant fibrovascular proliferation as these agents may worsen traction retinal detachment. Currently, a phase 3 prospective clinical trial is comparing prompt panretinal laser photocoagulation with intravitreal ranibizumab and deferred panretinal laser in PDR patients [57]. 2. Steroids: Inflammation plays an important role in the pathogenesis of diabetic retinopathy [58]. All the features of inflammation: increased blood flow, increased vascular permeability, tissue edema, leukostasis, microglial activation, macrophages and neutrophil infiltration, complement activation and increased cytokines (VEGF, TNFa, IL) have been reported in animal models as well as human diabetic retinopathy [59]. The inflammatory cytokines are upregulated in the serum, vitreous and aqueous samples in subjects with diabetic retinopathy. Inflammation can alter the BRB by acting on these steps in the cascade: (1) Increased expression of endothelial adhesion molecules such as ICAM1, VCAM1, PECAM‐1, and P‐selectin, (2) adhesion of leukocytes to the endothelium (leukostasis), (3) release of
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chemokines, and cytokines, (4) alteration of adherens and tight junctional proteins between the endothelial cells, and (5) infiltration of leukocytes into the neuro‐retina, resulting in the alteration of the blood retinal barrier [58]. Diabetic Macular Edema: The beneficial effects of steroids in DME are due to the fact that inflammatory cytokines and chemokines involved in the inflammatory cascade of DME are susceptible to steroids, whereas inhibition of VEGF itself may not result in neutralization of these molecules (Figure 2). The efficacy of intravitreal steroids in DME has been shown in the DRCR Protocol I. In this trial, the effect of intravitreal triamcinolone and laser was equivalent to that of ranibizumab and laser up to 24 weeks, and then the effect of triamcinolone gradually diminished because of increased rates of cataract formation [50]. In the subgroup of pseudophakic patients, the triamcinolone plus laser group was superior to the laser alone treatment and equivalent to the ranibizumab group [50]. In another randomized, multicenter three‐year long trial, the FAME study, intravitreal inserts of fluocinolone acetonide (0.2 ug/d and 0.5 ug/d) provided substantial benefit of visual improvement in patients with DME [59]. However, almost all patients receiving fluocinolone acetonide had cataract formation, and the incidence of incisional glaucoma surgery was 4.8% (low dose) and 8.1% (high dose). Although the US FDA did not approve this drug for DME because of its side effects, it has been recently approved in UK. It is interesting to note that the FAME study showed enhanced benefits of using fluocinolone acetonide in chronic DME (> 3 years duration) compared to nonchronic DME ( 5 letters in 56% of eyes receiving triamcinolon e vs. 26% of eyes receiving placebo58
b (0.5mg inj) improved visual acuity by >15 letters in 45.7% patients vs. 12.3% patients treated with sham injection37
13
Central Retinal Thickness
Fenofibrat e decreases progressio n of macular edema by 34% compared to placebo18
SDM equally as effective as conventional green laser (OCT measured central retina thickness of 255 vs. 248.9 um respectively) with less scarring55 Pascal laser equally as effective in treating CSME vs. conventional laser (28/30 vs. 27/30) 53 Pascal laser reduced FD-OCT by 20+/- 21 um at 3 months24 SDM and Pascal (double-frequency neodymium YAG laser 532 nm) have equally efficacy in reducing DME54
Intravitreal triamcinolon e injections are superior to posterior sub-tenon capsule injections in reducing foveal thickness59 Intravitreal triamcinolon e injections decreased macular thickness by a mean of 125 micrometers as compared to a mean decrease of 71 micrometers by placebo58
Ranibizuma b (0.5mg inj) decreased macular edema by 270.7 micrometer s compared to a decrease of 125.8 micrometer s in sham groups37 Ranibizuma b injections decreases foveal thickness less than laser therapy in DME36 44 patients receiving Ranibizuma b (0.5mg inj) received macular laser treatments vs. 94 patients in sham group37
Ranibizumab plus focal/grid laser reduced foveal thickness more than focal/grid laser alone in DME38,60
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Figure 1. Optical coherence tomography images of the study eye retina of a diabetic macular edema patient at baseline and months 1, 3 and 6. The patient received 0.3 mg of ranibizumab (Reproduced with permission from Chun et al Ophthalmology 2006; 113:1706‐1712).
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Figure 2. Pathophysiology and current strategies of therapies in diabetic macular edema (DME). Systemic factor control targeting blood glucose, blood pressure and lipids is still the gold standard treatment for diabetic retinopathy. Focal/grid laser is now indicated in those with non‐center involving DME only. Anti‐VEGF intravitreal injections are the first line of treatment in patients with center‐involving DME. Steroids are reserved for those who are poor responders to anti‐VEGF therapies. Finally, a small number of patients with vitreo‐macular traction are treated with vitrectomy surgery. Other potential novel target molecules are Ang‐2, CCL2, TNF‐α and IL‐1β. VEGF = vascular endothelial growth factor; Ang‐2 = angiopoietin 2; CCL2 = chemokine ligand 2; TNF‐α = tumor necrosis factor; IL‐1β = interleukin. DIABETES
Systemic Factor Control
Polyol, AGE, PKC & Hexosamine Pathway Activation
Hyperlipidemia
ROS INFLAMMATION Hypertension Growth Factors (VEGF), Chemokines & Cytokines (Ang-2, CCL2, TNF-α, IL-1β )
Anti-VEGF Therapies (for center-involving DME) Steroids
Altered Blood-Retinal Barrier
Increased vascular permeability
Focal/Grid LASER (for non-center involving DME)
Diabetic Macular Edema
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Vitrectomy
(for Vitreo-macular traction)
