Current Management of Diabetic Macular Edema

Diabetic macular edema is a complication of diabetes mellitus (DM) which contributes significantly to the burden of visual impairment amongst persons living with diabetes. Chronic hyperglycemia triggers a cascade of pathologic changes resulting in breakdown of the retinal blood barrier. Understanding the pathophysiological and biochemical changes occurring in diabetes has led to developing novel therapeutics and effective management strategies for treating DME. The clinical utility of optical coherence tomography (OCT) imaging of the retina provides a detailed assessment of the retina microstructure, valid for individualization of patient treatment and monitoring response to treatment. Similarly, OCT angiography (dye-less angiography), another innovation in imaging of DME, provides an understanding of retinal vasculature in DME. From the earlier years of using retinal laser photocoagulation as the gold standard for treating DME, to the current use of intravitreal injection of drugs, several clinical trials provided evidence on safety and efficacy for the shift to intravitreal steroids and anti-vascular endothelial growth factor use. The short durability of available drugs leading to frequent intravitreal injections and frequent clinic visits for monitoring constitute an enormous burden. Therefore, extended durability drugs are being designed, and remote monitoring of DME may be a solution to the current challenges. two doses of Ranibizumab with sham injections and confirmed the superiority of intravitreal Ranibizumab compared to sham injections. The study investigated using monthly Ranibizumab at two doses (0.5 and 0.3 mg) to treat DME. At month 24, the study results showed that 98% of patients-maintained vision with 0.3 mg monthly intravitreal injections, 34–45% of patients gained at least three lines (15 letters); and mean BCVA gain was 10.9 to 12.5 letters. Significantly higher numbers in the Ranibizumab arm gained >15 letters at month 24 compared to sham ie 44.8% vs. 18.1% in RISE; P < 0.0001, and 33.6% vs. 12.3%; P < 0.0001 in RIDE. Only 45–49% of patients needed macular laser compared with 91–94% in the control group. Also, there was no additional effect with the use of the higher strength 0.5 mg Ranibizumab when compared with the 0.3 mg dose. Efficacy in Ranibizumab versus sham in BCVA 20/40–20/160. mean versus a loss of 1.4 followed PRN over a 12-month follow-up. rescue compared to sham. both low- high-dose Flucinolone Acetonide DME and the risk- to-benefit was superior for the low-dose


Introduction
The rising number of persons living with diabetes worldwide has significant implications for global blindness. Diabetes is a condition of public health importance and paramount health concern in our time, with about 463 million adults worldwide living with diabetes as of 2019 [1]. The prevalence of diabetes for all age groups worldwide is 2.8% in 2000 and will increase to 4.4% in 2030 [2]. Projections suggest that the total number of individuals with diabetes will more than double from 171 million in 2000 to 366 million by 2030 [2]. Diabetic retinopathy (DR) is a microangiopathy and a significant finding amongst people living with diabetes. About 140 million patients are estimated to have diabetic retinopathy, and 10% of this number, i.e., about 14 million, have impaired vision. Diabetic macular edema (DME) is the commonest cause of visual impairment amongst persons living with diabetes [3]. non-fenestrated, and their endothelial cells have tight junctions which do not allow fluid leakage. A lymphatic system does not exist in the retina, but leakage can occur in the presence of retinal pathology, causing edema and swelling [32]. Chronic capillary non-perfusion and retinal ischemia are said to be the primary contributors to DME [33]. Signaling molecules such as insulin-like growth factor-1 (IGF-1), platelet-derived growth factor (PGF), angiopoietin, and most importantly, vascular endothelial growth factor (VEGF) all play a role in the subsequent development of diabetic microangiopathy [33].
The trigger for the vascular damage has been convincingly linked to the chronic hyperglycemia present in DM. Vessel damage occurs via the glucose metabolic pathways, which include the Diacylglycerol (DAG)-protein kinase C (PKC) pathway, Advanced glycation end-products (AGE), Polyol (sorbitol) pathway, Hexosamine pathway, and the plasma kallikrein-kinin system (KKS) [34][35][36]. The blood-retinal barrier (BRB) is an essential structure that regulates normal visual function [31,37]. It is a physiologic barrier that tightly regulates the balance of electrolytes, protein, solute, and water movement in and out of the retina. It is composed of both an outer and an inner portion [31,37]. The inner BRB comprises tight junctions between retinal capillary endothelial cells, basement membrane surrounding it, and pericytes outside [31,37]. The outer BRB tight junctions exist between retinal pigment epithelial cells located between them the fenestrated choriocapillaris and the outer retina [31,37].
In DME, disruption of the BRB is common, leading to increased vasopermeability associated with vascular leakage, neovascularization, and inflammation [38]. In chronic hyperglycemia, cellular and structural alteration in the BRB is characterized by the breakdown of cell-cell junctions between endothelial cells, pericyte loss, basement membrane thickening, increased deposition of extracellular matrix components, and Muller cell metabolism disturbance heralding the beginning of the microangiopathy [30,37,39]. Over time, continued retinal microvasculature damage results in the release of reactive oxygen species and inflammatory mediators and capillary nonperfusion, giving rise to retinal hypoxia and ischemia that drives upregulation of angiogenic factors, such as vascular endothelial growth factor (VEGF) and breakdown of the BRB [29,39]. The breakdown of the inner BRB then results in the accumulation of plasma proteins such as albumin, which exerts a high oncotic pressure in the neural interstitium, inducing interstitial edema, neural tissue impairment, and ultimately vision loss if there is a delay in treatment or no treatment at all [29,31,40].
Patients with DME have elevated vitreous levels of VEGF, Intracellular Adhesion Molecule-1 (ICAM-1), interleukin-6 (IL-6), and monocyte chemoattractant protein-1 compared to nondiabetic patients [41]. VEGF-A mediates angiogenesis by promoting endothelial cell migration, proliferation, and survival [41]. VEGF-A also possesses inflammatory properties through its capacity to mediate microvascular permeability and increase the adhesion of leukocytes. It has been noted to stimulate expression of ICAM-1 and vascular cell adhesion molecule −1 (VCAM-1), thus incorporating the inflammatory cascade, initiating early diabetic retinal leukocyte adhesion, and aiding the development of diabetic vasculopathy [39,41]. VEGF-A inhibitors have been shown to reduce vascular permeability [30,31]. Anti-VEGF agents such as Ranibizumab, Aflibercept, and Bevacizumab administered according to various treatment protocols are currently the gold standard for treating center-involving DME [31,37,42]. The introduction of intravitreal anti-VEGF therapy has led to notably improved outcomes for some patients with DR/DME [39]. Nevertheless, there are several practical limitations to the treatment with anti-VEGF. They include; cost, need for frequent intravitreal injections, undertreatment, and incomplete response in some patients [39,43].

Alternative pathways
Furthermore, clinical trials have demonstrated that only 33-45% of DME patients on intravitreal anti-VEGF agents showed three lines or more of visual improvement. Other DME patients showed an intermediate response (5-9 letters of improvement) or inadequate response (<5 letters of improvement or worse). Eyes with suboptimal early vision response showed poorer long-term visual outcomes than eyes with pronounced early response [37,44,45]. In the clinical setting, available data have shown that anti-VEGF therapy does not live up to the high goals set by clinical trials, leaving patients with suboptimal vision [46]. These limitations have resulted in exploring alternate pathways involved in aberrant angiogenesis, including the Tie-2 pathway and the effect of genetics [39].
The angiopoietin-tyrosine-protein kinase (Ang-Tie) system plays an essential and complementary role alongside VEGF-mediated vessel formation and vascular stability [42]. The angiopoietins, Ang-1 and Ang-2, are a family of growth factors that interact with one another to play a vital role in vessel homeostasis, angiogenesis, and vascular permeability via interacting with the Tie-2 transmembrane receptor tyrosine kinase [37,39,42]. Ang-1 plays a protective role in pathological angiogenesis, supports quiescent vessel maturation, and prevents intravesical inflammation [39,42]. In contrast, Ang-2 promotes vascular instability through its competition with Ang-1 and inhibition of Tie-2, contributing to DME [47]. Ang-2 is upregulated in response to hyperglycemia and plays a vital role in altering the BRB in DME [37]. Increased Ang-2 leads to decreased phosphorylation of Tie-2, which results in increased retinal vascular permeability [37]. Together Ang-2 and VEGF-A have been reported to produce accelerated neovascularization in the developing retina and ischemic retina [39].

Systemic control
The UKPDS and FIELD studies concluded that good control of modifiable risk factors of diabetic retinopathy delayed its development and progression [48][49][50][51]. Howbeit, findings of the ADVANCE trial came to a contrary conclusion [52]. Moreover, it has been observed in clinical practice that despite prolonged periods of poor control of glycemic and systemic blood pressure in some patients, DR was not observed, contrary to expectations. On the other hand, some other patients would develop DR within a relatively shorter period of diabetes, despite better control [53,54]. These observations suggest that mechanisms other than hyperglycemia, elevated blood pressure, and hyperlipidemia contributes to the development and progression of DME and diabetic retinopathy in some patients [55]. In addition, disparities in the risk of developing diabetic retinopathy have been noted among patients of different ethnic groups even after correcting for environmental factors, alluding to the fact that genetic factors may play a role in the pathogenesis of diabetic retinopathy [56][57][58][59]. This ethnic bias and variable predisposition bring to the fore the consideration of a concept of genetic predisposition to DME and DR in individuals of diverse ethnicity and genetic constitution.

Genetics of DME and DR
Gene mapping has been employed to identify novel genetic variants underlying DME and DR. However, only weak associations have resulted [55,60]. The Genomewide association studies (GWAS) had identified loci of interest MRPL19 and NRXN3 as novel loci with suggestive association with DME and PDR, respectively, which are sight-threatening complications of DR [61]. Although DR-associated genes have yet to be replicated and confirmed, these early findings represent the initial groundwork and maybe a preview of DR genetics' complexity [55,60,62].

Macular ischemia
Retinal ischemia has been recognized as a primary risk factor for developing proliferative diabetic retinopathy (PDR); it sometimes occurs with DME. A paucity of studies describing diabetic macula ischemia (DMI) exists, mainly due to difficulty in its detection using fluorescein angiography and limited treatment options [63]. Clinically, DMI is defined by an enlargement of the foveal avascular zone (FAZ) and paramacular areas of capillary nonperfusion [64]. Two anatomical changes can be characteristically seen in the retina of patients with DMI. First, due to marked cellular and extracellular damage, there is extensive loss of neuro-retinal tissue. Secondly, there is notable occlusion of the vessels supplying the retina [63]. DMI results in the upregulation of growth factors such as VEGF, which contribute to DME development [65], making it difficult to observe and anatomically characterize DMI in isolation. The anatomical and physiological basis of this disease is still very poorly studied [63]. Recently optical coherence tomography angiography (OCTA) offers a better image of macular microvasculature and is superior to conventional FA in assessing DMI. Anatomically the microcirculation supply to the retina is divided mainly into superficial capillary plexus (SCP) and deep capillary plexus (DCP) [66]. Choroidal circulation seems to be the most critical blood supply to the central macula, including the photoreceptor inner segment (IS) band, which appears to be the most critical consumer of oxygen [67]. It is thought that the DCP is responsible for up to 15% of the blood supply to the photoreceptors, especially during dark adaptation [65,66].

The classification of diabetic retinopathy (DR) and DME
The classification of diabetic retinopathy (DR) and DME have evolved over the years. About five decades ago, experts in ophthalmology gathered in Airlie House for a symposium to review the state of knowledge of DR; an outcome from that meeting was developing a standardized classification of DR [68][69][70]. Afterward, this classification was modified for use by the Diabetic Retinopathy Study (DRS) [69,70]. The modified Airlie House classification of diabetic retinopathy used in the DRS was further developed for the Early Treatment Diabetic Retinopathy Study (ETDRS). This randomized, prospective study evaluated the efficacy of laser treatment for macular edema [68]. It became the gold standard for many years. The ETDRS introduced the term clinically significant macular edema (CSME). CSME was defined using slit-lamp biomicroscopy, when it met any of the three criteria viz. "(1) thickening of the retina at or within 500 μm of the center of the macula; or (2) hard exudate at or within 500 μm of the center of the macula associated with thickening of the adjacent retina; or (3) a zone of retinal thickening one disc area or larger, any part of which is within one disc diameter of the center of the macula" [71]. After that, fluorescein angiography was used to guide laser treatment [72]. The ETDRS found that macular laser photocoagulation effectively reduced moderate visual loss by at least 50% in laser-treated eyes with CSME compared to untreated eyes [68,70]. In 2003, an international classification called the Diabetic macular edema disease Severity Scale with greater simplicity was proposed [29,73]. The DME disease severity scale put forward that DME is 'apparently present' when some apparent retinal thickening or hard exudates exist in the posterior pole; DME is proposed to be 'absent' otherwise [29,70]. When DME is present, it is classified into mild, moderate, or severe if the retinal thickening or hard exudate is distant from the center of the macula, approaching the center of the macula but not involving the center and involving the center of the macula, respectively [29,70]. Ten years after ETDRS, Optical Coherence Tomography (OCT) became the new imaging modality that enabled ophthalmologists to utilize the qualitative and quantitative measurement of central subfield macular thickness (CSMT) and visual acuity to diagnose and determine the response of DME to treatment [29,72]. OCT is invaluable due to its reliability and reproducibility; its importance in evaluating and monitoring DME cannot be over-emphasized [41,74].
A classification based only on slit-lamp biomicroscopic evidence of retinal thickening is grossly insufficient to precisely describe DME and determine the appropriate therapeutic modalities for the various morphologies [72,75].
Other parameters deployed by the OCT in DME diagnosis include retinal thickness, volume (quantitative data), and inner and outer layers of the retina [72,74].

Clinical presentation (symptoms and signs)
Patients with DME may be asymptomatic if the macula center is not involved. However, some eyes having center involving DME (CI-DME) have been seen to have no visual disturbance, presumably because of the recent involvement of the center [32]. Depending on the degree of fovea involvement and the chronicity of the edema, patients may present with an array of visual symptoms [32]. These include gradual progressive diminution and distortion of central vision over some time (usually moderate, unlike the severe loss after vitreous hemorrhage or retinal detachment involving the macula in proliferative diabetic retinopathy), metamorphopsia, and loss of color vision. They may also experience poor night vision and 'washing-out of vision in bright sunlight with poor dark-light adaptation [32,77,78].
On dilated biomicroscopic examination, retinal thickening may be observed in commonly identified patterns. Focal edema often occurs in association with a cluster of microaneurysms, sometimes surrounded by an incomplete ring of hard exudates. Diffuse DME may be very difficult to identify clinically if the retina is uniformly thickened due to the lack of reference landmarks. Clues include the height of the retinal blood vessels over the pigment epithelium, cystoids spaces, or even loss of the foveal depression. Other features that are sometimes seen with macular edema include variable loss of retinal transparency, a significant number of microaneurysms, intraretinal hemorrhages, and dispersed areas of hard exudates [32].

The control of systemic metabolic abnormalities
The control of systemic metabolic abnormalities observed in diabetes mellitus has a significant effect on the development and progression of diabetic microvascular complications, including DME [79]. The United Kingdom Prospective Diabetes Study (UKPDS) and the Diabetes Control and Complications Trial (DCCT) did demonstrate that optimal metabolic control could reduce the incidence and progression of DR [50,80]. To achieve good management of a patient with DME, a multidisciplinary approach involving different medical subspecialists such as ophthalmology, endocrinology, nephrology, neurology, cardiology, orthopedics is key [29]. Systemic workup involving blood investigations helps monitor the systemic status of these patients. These investigations including fasting blood glucose (FBG), glycosylated hemoglobin levels (HbA1C), serum electrolyte, urea, creatinine, and fasting lipid profile. Other investigations that may be required would be based on systemic complaints, examination findings, and other suspected comorbidities [29]. The recommended values for HbA1c, blood pressure, and LDL cholesterol are < 6.5-7%, <130/<85 mmHg, and < 100 mg/dl, respectively [81]. However, many patients fail to achieve or maintain these levels of metabolic control. In patients who significantly reduce HbA1c, there is an associated increased risk of severe hypoglycemia [33,50,80]. Managing physicians must recognize correctable risk factors of DR and DME, such as hyperglycemia, hypertension, and/or hyperlipidemia, to ensure appropriate monitoring and referral for eye care.

Ophthalmic evaluation
I. Over the last two decades, a wide range of imaging modalities, including fundus photography, fluorescein angiography (FA), optical coherence tomography (OCT), and OCT-Angiography (OCT-A), have been utilized not only for the diagnosis and classification of disease but also to monitor disease progression and treatment [82]. Figures 1-5 illustrate the significance of these imaging technologies in DR and DME. DME is diagnosed clinically with the slit-lamp biomicroscopy or indirect ophthalmoscopy with features such as visible microaneurysms, hard exudates, cysts, and retinal thickening. However, stereoscopic fundus photography and fluorescein angiography have greater sensitivity in detecting DME than ophthalmoscopy because of superior optics of the former, the enhanced contrast of fluorescein angiography, ability to make confirmation of vascular leakage, and the ability of the observer to evaluate magnified images without the interference of patients moving or blinking [83]. Stereoscopic fundus photographs provide an opportunity to evaluate and document long-term changes in the retina [32,82]. The ETDRS study used the 7 standard fields (7SF) 30° photographs of the retina (three horizontally across the macula and four around the optic nerve). This combination gave nearly 75° of visualization [29]. Mydriatic or nonmydriatic fundus imaging with ≥30 0 mono-or stereo photography is used with or without OCT [84]. Ultra-wide-field imaging is currently used for the screening and detection of DR, as is ultra-wide-field angiography [83].    Previously FFA helped predict prognosis and response to treatment in DME [59]. A case of diffuse DME was defined by fluorescein leakage involving most of the macula. This form of DME is more challenging to treat than focal DME involving  leakage from identified lesions [85]. FFA also revealed the degree of capillary non-perfusion and macular ischemia, shown by an enlarged foveal avascular zone [59]. With the development of ultra-widefield imaging, FFA can now be performed with visualization of up to 200° of the retina. Extensive ischemia in the retinal periphery has been associated with recalcitrant disease, and the ultra-widefield FFA may help identify DME that is likely to be treatment-resistant [59]. It reveals areas of peripheral ischemia and non-perfusion, which can be promptly treated with pan-retinal laser photocoagulation. The significant advantage of FFA is that it was the only imaging modality commonly used in DR that provides information on vascular flow and vessel permeability over time by visualizing leakage and pooling [82]. The disadvantage of FFA is that it is an invasive procedure that involves the administration of intravenous dye. It should be performed carefully, especially in patients with severe DR and associated systemic vascular complications such as severe renal disease and clinical or subclinical cardiovascular disease [29,82,86,87]. The most common adverse reactions are nausea and vomiting, but more severe side effects include localized reactions, urticaria, seizures, and, very rarely, anaphylaxis [29,82]. Before performing FFA, the ophthalmologist must carefully consider whether the information provided is necessary to make therapeutic decisions and whether the same or equivalent information can be provided by OCT which is noninvasive [83].
II. Since its first introduction, OCT has become the most frequently used diagnostic tool in ophthalmology for the past two decades and has revolutionized clinical imaging for diagnosis and disease management in most retinal diseases, including DME [78,82]. The diagnostic utility of the OCT can be seen in the case illustrated by Figures 6 and 7. The fast, non-invasive, high-resolution imaging available with OCT of the posterior segment allows for close study of the retinal anatomy and assessing retinal thickness profile and morphology in DME [82,83]. A significant advantage of OCT is that it can be easily repeated several times, within the same day, with a high degree of reproducibility. Therefore, it can be used to monitor the effect of therapy, e.g., intravitreal anti-VEGF given the same day or shortly after, to detect or objectively quantify response to therapy [82,83]. This value of the OCT to monitor treatment is illustrated with Figures 8 and 9. There are three types of OCT: time-domain (TD), spectral-domain (SD), and swept-source (SS) [82]. Spectral-domain OCT is the most commonly used, allowing three-dimensional raster scans of up to a few hundred B-scans, also creating highresolution images. It supersedes time-domain (TD)-OCT, the first generation that allowed imaging of 6 radial cuts only [78,83]. The most recent third-generation OCT technology uses a swept-source (SS) light source that allows high-speed imaging and provides three-dimensional raster images of high microstructural resolution, also referred to as optical histology [78]. OCT is highly sensitive and more accurate in  diagnosing DME when compared to fundus stereo photography and biomicroscopy [78], see Figures 1, 3 and 5. It is currently the gold standard for the diagnosis and monitoring of DME.
It is used to determine whether DME is center-sparing or center -involving, an essential criterion in determining treatment [78]. A limitation noted is that image segmentation could be a problem in eyes with marked DME and dome-shaped macula [88].
OCT not only identifies the presence or absence of disease activity such as the intra-retinal fluid (IRF) and the sub-retinal fluid (SRF) as seen in DME, it localizes them in the retina. It allows for quantification to assess the disease's response to anti-VEGF therapy [89], as demonstrated in Figure 9. It has been demonstrated that OCT using microstructural changes seen in IRF and SRF at baseline can prognosticate response to intravitreal treatments [90].
III. Certain features of retinal morphology seen on the SD-OCT, such as central subfoveal thickness (CST), vitreoretinal interface abnormalities, and the epiretinal membrane (ERM), can be used as surrogate markers and act as predictive factors for visual acuity (VA) outcomes in the treatment of DME [91][92][93]. CST was initially used as a predictor of visual outcome after treatment due to the ease of identifying and obtaining this parameter, but this had limitations [92]. Consequently, other aspects of OCT have been investigated to determine their usefulness as possible biomarkers and correlations for VA and treatment outcomes. These include an external limiting membrane (ELM) and ellipsoid zone (EZ) disruption, and disorganization of retinal inner layers (DRIL) [91,92]. Sun et al. described an OCT feature termed disorganization of the inner retinal layers (DRIL) [94]. It was observed that an improvement in DRIL following treatment for DME was predictive of better VA outcomes. There was an association with VA after the resolution of centre-involving DME [95,96]. An association between DRIL, the disruption of the outer retina, and increasing DR severity have been observed [91].
IV. The role of OCT-A is evolving as a tool in the evaluation of DME. OCT-A is an imaging technique that uses motion contrast and faster scan speeds, including spectral-domain (SD) and swept-source (SS), to obtain three-dimensional cubes, which then undergo automated segmentation into layers [82], as seen in Figure 10.
In DME, as with FFA, OCTA can visualize the increase in the size of the fovea avascular zone (FAZ) and perifoveal intercapillary area [97], seen in Figure 11. It can also   study the retinal vascular plexuses in layers, determine microvascular parameters, and correlate them with functional and morphological data [98].
The advantages of OCT-A are: It provides "3-D" imaging information of the macula and visualizes peripapillary capillaries [99]. It is dye-free, thereby suitable for patients with adverse reactions to the dyes and poor intravenous access or renal failure [100]. It is reproducible with a faster acquisition time [99,101]. An advantage of OCT-A over conventional FA is that the absence of dye leakage using OCT-A enables visualization of the distinct margins and sizes of neovascularization since there is no leaking of dye to obscure the neovascularization complex's margins seen in the later frames of the FFA [33]. The disadvantages of OCT-A include its inability to visualize leakage of dye in the retina, a common feature of inflammatory vascular pathology, and a sign of blood-retinal barrier breakdown [100]. Limitation to detecting peripheral retinal ischemia as it can scan mostly the posterior pole [100]. Studies suggest that in the future management of DME, OCT-A could be used to prognosticate the evolution of visual acuity with the help of biomarkers such as low vascular density (VD) and enlargement of the foveal avascular zone (FAZ) [102-104]. OCT-A could also be used to aid in the monitoring of the response of DME to anti-VEGF treatment such as Ranibizumab since poor responders show significant damage to the DCP, but not SCP [105,106].
Initially, the major limitation of OCTA was the small field of view, with the greatest resolution achieved at smaller scanning sizes such as the commonly used 3 × 3 mm scan [33,82]. Wider field OCTA scans are already available such as the 9 × 9 mm and 12 × 12 mm. Experimental wide-field OCTA using faster scanning OCTA is being researched and could be available in the future [102,103,107].
Other drawbacks noted are that OCTA is subject to projection artifacts. Vasculature from outer layers is projected onto the deep plexuses and choriocapillaris, affecting the accurate interpretation of vascular pathology in the deeper layers. It is also prone to movement artifact; patient movement presents as horizontal white lines, and artifact blinking appears as black lines across the image [83]. Solutions to artifacts include the incorporation of software to correct the motion artifacts [108].
Visual acuity is still viewed as the gold standard in clinical settings for assessing vision using the Snellen or ETDRS charts, but it does not entirely reflect functional vision [109,110]. Functional vision depicts the impact of sight on the quality of life as expressed by the patient [109]. Various visual function disturbances such as waviness, relative scotoma, and reduction in contrast sensitivity are known to precede loss of visual acuity in patients with DME. However, they are not assessed and quantified during a routine eye examination. For assessing these abnormalities, microperimetry is used to identify vision-threatening retinopathy before visual acuity is affected. Microperimetry is a diagnostic tool used to assess retinal sensitivity while the fundus is directly examined; it enables exact topographic correlation between macular pathology and corresponding functional abnormality [109,110]. It is rapid, safe, and non-invasive [110]. Microperimetry is of value in prognosticating the functional outcome as foveal thickness returns to normal following the treatment of DME [109]. Microperimetry has been used to demonstrate low retinal sensitivity present in the areas of capillary drop out in eyes with ischemic DME [111].
Multifocal electroretinogram is an electrophysiologic test. It is used to objectively identify functional changes of the retina in the early phases of DR and DME [112] and is also helpful for objectively monitoring eyes on intravitreal antiVEGF treatment such as Ranibizumab for DME [113].

Systemic control
The control of all systemic risk factors is vital in the treatment of DME. Optimizing control of diabetes, hypertension, and serum lipids should be emphasized. Optimization of care involves visits to the internist. The intervention aims to reduce glycated hemoglobin, elevated blood pressure, and elevated serum lipids to produce measurable effects in macular thickness in as little as six weeks [114].
The Diabetes Control and Complications Trial (DCCT) reported that tight blood glucose control in patients with type 1 diabetes reduced the cumulative incidence of macular edema at 9-year follow-up by 29% and reduced the application of focal laser treatment for DME by half [115,116].
The United Kingdom Prospective Diabetes Study (UKPDS), a randomized clinical trial of patients with type 2 diabetes, reported that tighter blood glucose control reduced the requirement for laser treatment at ten years by 29%, compared with looser control; 78% of the laser treatments were for DME [50]. This study also demonstrated that a mean systolic blood pressure reduction of 10 mm Hg and a diastolic blood pressure reduction of 5 mm Hg over a median follow-up of 8.4 years led to a 35% reduction in retinal laser treatments 78% were for DME [51].
The Action to Control Cardiovascular Risk in Diabetes (ACCORD) eye study compared the progression of DR in a Simvastatin plus placebo group, Simvastatin plus fenofibrate group. The rate of progression of DR was lower in the fenofibrate group than in the placebo group [117].
High plasma cholesterol may be associated with more severe hard exudates at the macula [118,119]. It has been reported that oral Atorvastatin reduced lipid migration to the subfoveal region and decreased the severity of hard exudates in type 2 DM patients with dyslipidemia who had CSME [120]. Nephropathy and anemia can contribute significantly to the risk of DR and DME. Weight loss and cessation of smoking are also crucial in preventing DR and DME.

Observation
The DRCR Network, Protocol V study, addressed the management of well-controlled DM with center involving DME (CI -DME) and good vision. Randomization of study participants was to observation, focal laser, and intravitreal Aflibercept [121]. The results suggest that patients with CI-DME and good vision (20/25 or better) can be managed initially with observation and close followup. These eyes should receive treatment if they suffer a decrease in vision.
For many years, focal and or grid macular laser photocoagulation (MLP) was the gold standard for DME treatment; newer laser techniques are now available. These minimize the side effects of a traditional laser. Intravitreal anti-Vascular endothelial growth factor (anti-VEGF) injections are now the mainstay of CI-DME. Although intravitreal anti-VEGFs have become popular, intravitreal steroids are often indicated in the treatment of DME. Vitrectomy is also used to treat DME. Combination therapy is another strategy employed for treating DME.

Intravitreal anti-vascular endothelial growth factors (anti VEGF).
Anti VEGFs inhibit upregulated VEGF, which has been implicated in the pathogenesis of DME. The efficacy of anti-VEGF injections in DME has been demonstrated by several studies [122][123][124][125]. Anti-VEGF therapy, however, requires frequent intravitreal injections that are difficult to transpose to clinical practice. Thus, fewer injections are administered in clinical practice than in clinical trials; this contributes to decreased efficacy as the results of clinical trials have been difficult to replicate in real life [126].

Pegaptanib
The first anti-VEGF drug used to treat DME was Pegaptanib (Macugen®, Bausch and Lomb, Rochester, NY, USA), which selectively blocks the 165-isoform of VEGF [127]. A phase II trial by the Macugen Diabetic Retinopathy Study Group reported that at 36 weeks, Pegaptanib led to better BCVA gain, a more significant reduction in central macular thickness (CMT), and less requirement for laser in DME when compared to sham [128]. However, it has been observed that Pegaptanib is less effective at improving visual outcomes than other anti-VEGF agents that target all VEGF-A isoforms [129].

Bevacizumab
Bevacizumab, a humanized monoclonal antibody that inhibits VEGF, was initially developed as a concomitant medication for use in combination with existing metastatic colorectal cancer regimens [130]. The FDA does not approve it for the treatment of DR or DME. However, the intravitreal Bevacizumab or laser therapy in the management of diabetic macular edema (BOLT) study examined the efficacy of Bevacizumab versus focal laser for DME and reported that Bevacizumab is superior to focal laser alone [131].
Patients in the Bevacizumab group showed significant BCVA improvement over patients in the laser group [131]. Bevacizumab costs much less than the FDAapproved intravitreal anti-VEGF drugs [132]. It is, therefore, more cost-effective in treating DME than Ranibizumab or Aflibercept [133,134]. It is usually given as a 1.25 mg in 0.05 ml dose. The incidence of severe ocular and monocular adverse events was low for intravitreal Bevacizumab [135].

Ranibizumab
Ranibizumab (IVR, Lucentis®, Novartis, Basel, Switzerland) is a fully-humanized monoclonal antibody fragment that binds to VEGF-A's multiple variants [136]. The Ranibizumab for Diabetic Macular Edema (A Study of Ranibizumab Injection in Subjects With Clinically Significant Macular Edema With Center Involvement Secondary to Diabetes Mellitus (RIDE) and A Study of Ranibizumab Injection in Subjects With Clinically Significant Macular Edema With Center Involvement Secondary to Diabetes Mellitus (RISE) trials investigated the use of monthly Ranibizumab given in two doses-0.5 and 0.3 mg-for the treatment of DME [137]. The FDA approves it for the treatment of DME and DR at a dose of 0.3 mg monthly.
Port Delivery System (PDS) with Ranibizumab is a permanent refillable eye implant, approximately the size of a grain of rice, designed to deliver a customized formulation of Ranibizumab continuously over an extended duration, i.e., six months; potentially reducing the treatment burden associated with frequent eye injections [138].
The LADDER trial demonstrated that PDS with the 100 mg/mL formulation is non-inferior to monthly intravitreal injections of Ranibizumab in terms of visual and anatomical outcomes in neovascular age related macular degeneration (AMD) eyes [139]. In the ARCHWAY trial, 98.4% of PDS patients could go six months without needing additional treatment and achieved vision outcomes equivalent to in AMD patients receiving monthly Ranibizumab injections, a current standard of care [138]. Therefore, PDS could reduce the number of anti-VEGF treatments to two per year.
It is surgically implanted via a specialized tool through an incision in the sclera and pars plana. Reported adverse effects include conjunctival bleb, vitreous hemorrhage, conjunctival erosion, conjunctival retraction, endophthalmitis, rhegmatogenous retinal detachment, and hyphaema [138].
Two trials, PAGODA (will evaluate the efficacy, safety, and pharmacokinetics of the PDS With Ranibizumab in participants with DME compared with intravitreal Ranibizumab) and PAVILION (a multicenter, randomized study in participants with diabetic retinopathy without center-involved DME to evaluate the efficacy, safety, and pharmacokinetics of Ranibizumab delivered via the PDS relative to the comparator arm) are underway to study the safety and efficacy of PDS in subjects with DME and those with DR without CI-DME [140,141].

Aflibercept
Aflibercept (IVA; VEGF-trap eye, Eylea, Regeneron Pharmaceuticals, NY, USA) is a recombinant chimeric fusion protein containing the second domain of VEGFR-1 and the third domain of the VEGFR-2 attached Fc portion of human IgG1 [142]. It has a dimeric structure, the molecular weight of the protein is 97kD, and the total molecule after glycosylation is 115kD [143]. Aflibercept acts as a decoy receptor binding VEGF-A, VEGF-B, and PlGF, thereby preventing their binding with their original receptors [144]. VEGF-A binds to both VEGFR-1 and VEGFR-2, but PlGF binds to only VEGFR-1. The FDA approves it for the treatment of DME and DR in patients with DME at a dose of 2 mg. It was studied in the Intravitreal Aflibercept for Diabetic Macular Edema (VISTA and VIVID) trials which compared Aflibercept with a focal laser to treat DME [145]. These studies demonstrated the superiority of Aflibercept over laser in terms of visual acuity improvement.
A comparative effectiveness randomized clinical trial compared Bevacizumab with Ranibizumab and Aflibercept for DME and found that all three agents are effective treatments at the two-year follow-up [146]. However, in eyes with visual acuity of 20/50 or worse, Aflibercept was superior to Ranibizumab and Bevacizumab at one year. In contrast, at two years, Aflibercept was no longer superior to Ranibizumab but remained superior to Bevacizumab [132,147].
A concomitant effect of intravitreal anti-VEGF treatment for DME noticed with Ranibizumab and Aflibercept is improvement in retinopathy severity or slowing of the rate of progression of retinopathy [148]. Another concomitant effect is thinning of the choroid [149,150].

Brolucizumab
Brolucizumab (IVBr, Beovu; Novartis; Basel, Switzerland), a single-chain antibody fragment, was approved for the treatment of nAMD in October 2019 and in February 2020 in the USA and the European Union [151]. The potential benefits of Brolucizumab are assumed to be related to its low molecular weight with subsequent better tissue penetration as well as higher molar concentration [152,153]. Its use is mentioned here for completeness. It is no longer in "popular" use due to safety concerns. Brolucizumab was associated with reports of intraocular inflammation (IOI) and retinal vasculitis with or without occlusion [154,155].
Positive 1-year results of the phase III KESTREL and KITE studies, evaluating the efficacy and safety of Beovu (Brolucizumab) 6 mg in DME were reported. Both studies met their primary endpoints of noninferiority in the change in BCVA from baseline for Beovu 6 mg versus Aflibercept 2 mg at year one [156]. However, the Beovu trials have been discontinued because Beovu was associated with higher rates of intraocular inflammation, including retinal vasculitis and retinal vascular occlusion versus Aflibercept [157].

Faricimab
Faricimab is a novel anti-Ang-2/anti-VEGF bispecific antibody designed explicitly for intraocular use [158,159]. It is assembled using Roche's CrossMAb technology (Basel, Switzerland) and binds both VEGF-A and Ang-2 with high affinity and specificity [158,160]. Faricimab is the first investigational bispecific antibody designed for the eye [161].
It targets two distinct pathways -via angiopoietin-2 (Ang-2) and vascular endothelial growth factor-A (VEGF-A) -that drive several retinal vascular diseases [161]. Ang-2 and VEGF-A contribute to vision loss by destabilizing blood vessels, causing new leaky blood vessels to form and increasing inflammation [162]. By simultaneously blocking both pathways involving Ang-2 and VEGF-A, Faricimab is designed to stabilize blood vessels, potentially improving vision outcomes for a longer duration in patients living with retinal conditions [162].
Faricimab is a promising molecule that is still undergoing investigation primarily for nAMD. The STAIRWAY Phase 2 Randomized Clinical Trial concluded that at week 52, Faricimab dosing every 16 weeks and every 12 weeks resulted in maintenance of initial vision and anatomic improvements comparable with monthly Ranibizumab [163]. TENAYA and LUCERNE phase 3 trials evaluate the efficacy, safety, and extended durability of up to 16 weekly dosing of intravitreal Faricimab in patients with nAMD [164]. YOSEMITE and RHINE are ongoing trials evaluating the efficacy, durability, and safety of Faricimab 8 weekly or a protocol-driven regimen based on treat-and-extend in DME patients [165]. Positive first-year results have been reported for Faricimab, which may emerge as an essential option if equivalent second-year results are reported with no safety flags.

Regimens
There is no consensus about the ideal treatment regimen with anti-VEGF agents [166]. Different treatment algorithms have been studied in clinical trials for AMD and applied in clinical practice, including monthly injections (ANCHOR, MARINA, CATT, HARBOR, EXCITE, IVAN, VIEW) as needed 'pro re nata' PRN (SUSTAIN, MONT BLANC, SAILOR, CABERNET, PrONTO, IVAN, CATT, HARBOR, OCTAVE), and 'treat and extend' regimen (TREND, LUCAS) [167].
Monthly maintenance dosing is a tremendous burden for both patients and the healthcare system. It has a real risk of overtreatment. The pro re nata (PRN) regimen is a treatment protocol where follow-up intervals remain fixed. At the same time, decisions to carry out an injection are based on the anatomic findings at each respective visit [168]. The PRN regiment has a risk of undertreatment or overtreatment, and patients may fail to attend. A treat-and-extend regimen (TER) is an individualized dosing scheme of titrating the injection interval based on the patient's response [169]. Therefore, if a patient shows no sign of active disease (e.g., the macula remains dry, without any leakage), intervals will be extended; if there is fluid accumulation, the next interval will be shortened. Fixed dosing lacks long-term practicability in real-world settings due to overtreatment and high costs; thus, PRNs or TERs have been suggested as feasible alternatives [169]. TERs have advantages: their cost-effectiveness due to less frequent visits and increased efficacy based on proactive treatments. However, TER involves more injections than a PRN regimen, leading to overtreatment [170].

Side effects of intravitreal injection of anti VEGFs
Endophthalmitis, intraocular inflammation (IOI), rhegmatogenous retinal detachment, intraocular pressure elevation, and ocular hemorrhage have been reported as complications of intravitreal anti-VEGF injections [171]. There are reports of ocular inflammatory events with Brolucizumab intravitreal injection [172,173]. Recently, occlusive retinal vasculitis has been reported with the use of Brolucizumab. For this reason, the use of Brolucizumab has been discontinued. Furthermore, the experience with Brolucizumab has increased the surveillance by an ophthalmologist of drug-related IOI.
Intraocular silicone oil droplets and protein aggregates have also been reported with intravitreal anti-VEGF injections [174]. Several systemic adverse events of anti VEGFs have been reported in different studies, including systemic hypertension, cerebrovascular accidents, heart attacks, and death [175,176].
About 40-60% of eyes that receive anti-VEGF injections show an insufficient response with recurrent and persistent macular edema, even after repeated injections [177,178].

Corticosteroids
Corticosteroids inhibit leukostasis, adhesion, transmigration of leukocytes and downregulate the expression of prostaglandins, cytokines, and growth factors, especially VEGF [179]. They also alter the composition of the basal endothelial membrane by changing the local ratio of laminin isoforms, suppressing basement membrane dissolution, and strengthening tight junctions to limit permeability and leakage [180]. Long-term steroid use may have a neuroprotective effect on the retina [181].
Corticosteroids are now usually second-line therapy. Some of the indications for intravitreal steroids in DME include non-response to anti-VEGF, non-compliant patients, pregnancy, history of recent arterial thromboembolic events (ATEs), patients with hard exudates (HE) at the center of the fovea, pseudophakic patients (there is no risk of cataract) and vitrectomized eyes [182]. In vitrectomized eyes, corticosteroid intravitreal implants release drugs at a constant rate and provide predictable pharmacokinetics [183,184].
In clinical trials that studied the use of intravitreal steroids in treating DME, pseudophakic eyes were shown to have better visual acuity (VA) outcomes than phakic eyes [185,186]. The DRCRnet, protocol U concluded that pseudophakic patients with persistent DME showed better VA outcomes with combination treatment of Ranibizumab and Dexamethasone intravitreal (DEX) implant compared with Ranibizumab alone [187].

Dexamethasone sustained-release implants
Dexamethasone intravitreal (DEX) implant (0.7 mg) (Ozurdex, Allergan, Inc., Irvine, CA, USA) consists of micronized dexamethasone in a biodegradable copolymer of polylactic-co-glycolic acid, which slowly releases steroids into the vitreous for about 6 months [188,189]. In 2014, based on the results of the MEAD study [190], the FDA and most European countries approved Ozurdex for the treatment of DME. DEX is a potent anti-inflammatory agent; its potency is twice that of Fluocinolone acetonide (FA) and 5-fold more than Triamcinolone Acetonide (TA) [191]. In contrast to TA, the pharmacokinetics of the DEX implant were not significantly different in vitrectomized and nonvitrectomized animal eyes [192]. There have been reports of the benefits of using DEX implant in naive DME as a first-line option [193,194] and the advantages of early switching in patients not responding to anti-VEGF [195].

Fluocinolone acetonide (FA) implant
FA has a 25-fold higher anti-inflammatory potency than cortisol [196]. It has selective and potent agonist properties by binding to the cytosolic glucocorticoid receptor with high affinity; it is devoid of mineralocorticoid activity [197][198][199]. FA is available as an intravitreal implant. It is small (3.5 mm in length, 0.37 mm in diameter), non-biodegradable, and designed for injection using a 25-gauge injector via the pars plana into the vitreous cavity [200]. The approved implant (ILUVIEN®) contains 0.19 mg of FA initially released at 0.25 μg/day (average, 0.2 μg/day); it lasts 36 months [201]. The Fluocinolone Acetonide for Diabetic Macular Edema (FAME) studies evaluated the use of 2 different FA doses (0.2 vs. 0.5 μg/day) compared to sham injections [202,203]. This study showed the efficacy of FA implants for chronic DME that is resistant to conventional treatment.

Triamcinolone Acetonide (TA)
TA has a 7.5-fold higher anti-inflammatory potency than cortisone [204]. It was the first widely used intravitreal injectable medication for DME [205]. Several clinical trials have shown the efficacy of TA in the treatment of DME [206][207][208]. TA Half-life in the vitreous of a nonvitrectomized eye has been reported as 18.6 days, in contrast to a much shorter duration in a vitrectomized eye, 3.2 days [209]. A single intravitreal injection of 4 mg of TA lasts approximately three months in the nonvitrectomized human eye [209,210]. DRCR.net Protocol B investigated the efficacy and safety of 1 mg and 4 mg doses of TA compared with focal or grid laser photocoagulation and concluded that focal laser was superior to intravitreal triamcinolone [211,212].

Adverse effects
Adverse effects of intravitreal steroids include ocular hypertension, cataract, infectious endophthalmitis, pseudo endophthalmitis, and sterile endophthalmitis [213]. A steroid-induced cataract is the most common adverse event of intravitreal corticosteroids [213]. Up to 50% of eyes injected with intravitreal corticosteroid will develop elevated intraocular pressure [214,215]. Both the DEX and FA implants have been reported to migrate into the anterior chamber, potentially leading to corneal edema, corneal endothelial decompensation, and ocular hypertension [216,217]. The DEX implant has been accidentally injected into the crystalline lens rather than into the vitreous cavity [218]. In terms of outcomes, Gillies et al. reported that the Dexamethasone implant (Ozurdex, Allergan) was as efficacious as Bevacizumab in reducing DME [219].

Macular laser photocoagulation (MLP)
MLP was the first proven treatment for DME [220,221]. Though its mechanism of action is not entirely understood, it improves DME through several proposed mechanisms. Photoreceptors and retinal pigment epithelium RPE cells are destroyed via a photothermal mechanism, thus reducing oxygen consumption. The reduced oxygen consumption in the outer retina is postulated to increase oxygen flux from the choroid to the inner retina, causing arteriolar constriction and decreased hydrostatic forces that drive edema [222].
Photocoagulation also induces changes to the RPE cells, causing their proliferation and releasing cytokines such as transforming growth factor-beta TGF-β, which antagonize the effects of VEGF [223].
The Early Treatment Diabetic Retinopathy Study (ETDRS) demonstrated a 50% reduction in moderate vision loss in patients with clinically significant diabetic macular edema (CSME) who underwent immediate focal laser photocoagulation [221]. MLP causes iatrogenic tissue damage, subretinal fibrosis, choroidal neovascularization, and laser scar enlargement [224,225].
The DRCR.net re-examined this coagulation technique and reported it as a modified (m) ETDRS focal/grid photocoagulation protocol [226], but the risk of macular tissue damage remained.
The DRCR.net Protocol A reported that mETDRS laser is better than modified macular grid laser for DME while DRCR.net Protocol B noted that mETDRS focal laser is superior to intravitreal triamcinolone for DME [227]. DRCR.net Protocol K also reported that 20-60% of eyes that initially respond to focal laser might continue to improve after four months, suggesting durability of effect [228]. The macular laser had been considered the gold standard for many years [229]. According to the European Society of Retina Specialists (EURETINA) guidelines, focal/grid laser is now reserved mostly for non-center-involving DME [78].

Subthreshold micropulse diode (SDM) laser photocoagulation
SDM has been used in the treatment of DME [230][231][232]. Compared with conventional laser photocoagulation, SDM is a tissue-sparing technique: it avoids protein coagulation and prevents retinal scars, allowing retinal anatomic and functional preservation [233]. It has been hypothesized that SDM, by inducing a controlled thermal elevation of the retinal tissue, can selectively stimulate the retinal pigment epithelium (RPE) [234,235]. Its advantages include the absence of RPE scarring, no subsequent choroidal neovascularization, and elimination of paracentral visual field scotomas [232,236]. Its disadvantages include no visible endpoint for treatment, making it difficult to determine where treatment has and has not been applied. Furthermore, there is no standardized, consensus set of treatment parameters or guidelines for treatment within the foveal avascular zone. The reduction in macular edema after subthreshold laser photocoagulation occurs with a slower time course, and more treatments are necessary to eliminate edema [232]. Some randomized clinical trials have demonstrated that subthreshold grid laser treatment is as effective as conventional focal/grid laser photocoagulation, though slower in terms of resolution of DME, in achieving the same functional and anatomical effects [237,238]. There have been reports of the benefits of combining SDM and intravitreal anti VEGFs in treating DME [239,240].

Selective retinal therapy (SRT)
SRT is a laser procedure in which the RPE is selectively damaged without affecting the neural retina and choroid [241][242][243]. A microsecond pulsed laser is used to induce an instantaneous temperature rise just at the melanosomes within RPE cells, which leads to the formation of microbubbles around these melanosomes. Their temporary expansion results in a cell volume expansion and eventually mechanical cellular disruption without increasing temperature in the surrounding tissue. Studies have shown that SRT is effective in treating DME [243,244].

Patterned scanned laser (PASCAL)
In PASCAL, the shorter pulse duration is used in an array of multiple burns to provide speed, better spatial localization, and reduced collateral damage by providing more precise control of the depth of the impact [245]. PASCAL is an ideal laser method to place the accurate "subthreshold" (subvisible) focal-grid laser in DME in contrast to conventional laser therapy [246,247]. The advantages of PASCAL over conventional laser therapy include shorter treatment duration, increased safety, uniform, and precise spot placement, accurate "subthreshold" grid-pattern placement, and reduced pain and visual field defect [248]. However, the efficacy of PASCAL laser appears to be diminished compared to conventional laser therapy when the same number of laser spots were delivered [249].

Navigated laser (NAVILAS)
NAVILAS is a fundus imaging and laser treatment device developed by Neubauer et al. (OD-OS GmbH, Teltow, Germany) [250,251]. The device utilizes retina navigation via computerized image capture and tracking assistance with high precision and reproducibility of <60-110 um [250]. It appears that the rate of retreatment for DME is reduced with NAVILAS when compared to the conventional mETDRS focal laser technique [251].
A 92% hit rate of microaneurysm via NAVILAS compared to 72% in conventional laser focal coagulation has been reported [252]. Focal laser therapy using NAVILAS will have more impact in the future to improve visual acuity and reduce the burden of anti-VEGF injection numbers in patients [253,254].

Vitrectomy for DME
Optical coherence tomography has shown that vitreomacular adhesion is a risk factor for DME [255], as illustrated in Figure 5. Complete separation of posterior hyaloid with Posterior Vitreous Detachment (PVD) is associated with a decreased rate of DME [256]. Vitrectomy removes traction, improves macular oxygenation, removes VEGF and pro-inflammatory cytokines, and allows additional endolaser and steroids placement [257]. It was introduced for treating eyes with a taut posterior hyaloid adherent to the macula, often associated with shallow traction macular detachment, which had failed previous focal/grid laser [258,259], as can be seen in Figure 5. It has also been used to treat eyes with an attached but non-thickened, non-taut posterior hyaloid or for eyes with persistent DME despite previous focal laser or intravitreal triamcinolone injection regardless of the status of the posterior hyaloid [260,261], Illustrated in Figures 12 and 13.
Vitrectomy has been used as a potential primary therapy in eyes with more severe edema and greater visual acuity loss at presentation [262,263]. Reports on the outcome of vitrectomy for DME are conflicting; some reports suggest that vitrectomy reduces macular thickening but does not improve visual acuity [264,265]. Others have report improved visual acuities simultaneous with decreases in macular thickening or lagging behind the reduction in macular thickness by a few months [266,267]. There have also been reports of improved visual acuity in cases with macular traction but no visual improvement in cases without traction [268,269].

Plasma kallikrein inhibitors
Plasma kallikrein is highly upregulated in vitreous patients with DME [270]. It is a mediator of vascular leakage and inflammation. There is evidence that it is involved in DME pathogenesis in VEGF independent fashion and VEGF interdependent mechanisms [271]. Several small molecules and bicyclic peptides targeting the plasma kallikrein/kinin system are currently under investigation for DME treatment via intravitreal, oral, and topical administrations [271]. These include KVD001 (KalVista Pharmaceuticals) a highly potent and selective plasma kallikrein inhibitor, currently being developed as an intravitreal therapy), THR-149 (Oxurion NV), RZ402 (Rezolute Bio), and VE-3539 (Verseon Corp) [271]. Orally administered plasma kallikrein inhibitors are efficacious in reducing retinal edema and preserving retinal function in preclinical models. Plasma kallikrein inhibition is emerging as a promising new treatment modality for DME [271].

Clinical Studies in DME
The evidence for much of the guidelines on DME management has been gathered from clinical trials that have provided information on the safety and efficacy of different therapeutic options, investigated the systemic associations in patients diagnosed with DME, and considered newer and better therapies. This section will provide an overview of DME trials and emphasize the most important findings. Emphasis will be placed on those pharmacotherapies in current use (especially intravitreal injectable drugs).
As mentioned earlier, VEGF plays a central role in the pathogenesis of DME by increasing vascular permeability and blood flow in the setting of microvascular damage secondary to prolonged hyperglycemia. Therefore, intravitreal anti-VEGF has become the standard of care in the treatment of several forms of DME. In many cases, DME can be reversed, and this is associated with sustained improvements in vision. Several RCT have provided data and evidence for the use of intravitreal anti-VEGFs.
Ranibizumab (Lucentis, Genentech, South San Francisco, CA, USA) has been described earlier. It has a molecular weight of approximately 48 kilodaltons as it lacks an Fc region, unlike Bevacizumab. It is prepared in Escherichia coli with tetracycline in the nutrient medium. Due to its relatively small size, Ranibizumab penetrates the deeper layers of the retina, including the RPE and choroid.
Ranibizumab was the first anti-VEGF approved by the US Food and Drug Administration (FDA) for the treatment of DME and DR at a dose of 0.3 mg monthly. Also, the 0.5 mg dose has been used for treating DME. The 0.3 mg is as effective as the 0.5 mg. Also, the higher dose was found to confer no additional benefit compared to the 0.3 mg but was associated with more fatalities at three years (i.e., 6.4% compared to 4.4% with 0.3 mg monthly). Furthermore, at three years reported stroke rate was 4.8% and 2%; and adverse thromboembolic events (ATE) were 10.4% and 10.8% with monthly 0.5 mg and 0.3 mg Ranibizumab, respectively. Because of these systemic risks, the FDA approved the 0.3 mg dose of Ranibizumab instead of the 0.5 mg dose. However, a reduced dose is not available for other available anti-VEGF, i.e., Bevacizumab or Aflibercept. It is, however, essential to consider that the occurrence of these systemic adverse events is not uncommon after prolonged diabetes. RISE  two doses of Ranibizumab with sham injections and confirmed the superiority of intravitreal Ranibizumab compared to sham injections. The study investigated using monthly Ranibizumab at two doses (0.5 and 0.3 mg) to treat DME. At month 24, the study results showed that 98% of patients-maintained vision with 0.3 mg monthly intravitreal injections, 34-45% of patients gained at least three lines (15 letters); and mean BCVA gain was 10.9 to 12.5 letters. Significantly higher numbers in the Ranibizumab arm gained >15 letters at month 24 compared to sham ie 44.8% vs. 18.1% in RISE; P < 0.0001, and 33.6% vs. 12.3%; P < 0.0001 in RIDE. Only 45-49% of patients needed macular laser compared with 91-94% in the control group. Also, there was no additional effect with the use of the higher strength 0.5 mg Ranibizumab when compared with the 0.3 mg dose.
In the RISE and RIDE extension phase, patients in the sham control group could cross over and receive monthly Ranibizumab injections in the 3rd year. The 36-month outcomes demonstrated that the rapid and sustained response of Ranibizumab in DME is further maintained for an additional 3rd year of continued monthly treatment. In addition, the group with delayed initiation of Ranibizumab therapy gained fewer letters compared to groups initially randomized to receive Ranibizumab (+4.7 vs. +10.6 letters in the 0.3 mg Ranibizumab arm). This finding suggests that chronic retinal edema (for an average of 4.5 years before Ranibizumab therapy) may result in irreversible loss of vision, and therefore prudent to initiate Ranibizumab therapy earlier. The RISE and RIDE study has become a vital landmark study against which other studies investigating more recent intravitreal pharmacotherapies have been compared.
RESOLVE: Safety and Efficacy of Ranibizumab in Diabetic Macular Edema With Center Involvement. This trial compared Ranibizumab versus sham in DME patients with BCVA of 20/40-20/160. It showed a better mean gain in letters with Ranibizumab than sham (10.3 letters gain versus a loss of 1.4 letters respectively). The patients were given three monthly injections, followed by PRN injections over a 12-month followup. A rescue laser could be performed if needed. CMT reduction was also more with Ranibizumab compared to sham. This study also suggested that Ranibizumab treatment was superior to laser (7.8 ETDRS letters gained versus −1.7 ETDRS letters lost).
READ-2: Ranibizumab for Edema of the mAcula in Diabetes-2). This study was A phase II, RCT to compare Ranibizumab alone (group 1), the focal laser alone (group 2), and combination of laser and Ranibizumab (group 3), i.e., randomized patients 1:1:1 to receive 0.5 mg Ranibizumab, laser, or both. Inclusion criteria were BCVA of 20/40-20/320 and CSMT of 250microns. The study demonstrated a BCVA gain of 7.4 letters in the RBZ arm at three months compared to 0.5 letters in the laser arm.
Change in mean BCVA in ETDRS letters at six months for the three groups was +7.24, −0.43, and + 3.8, respectively. However, at 24 months, it was demonstrated that Ranibizumab alone or in combination was superior to laser alone in DME.
READ-3 study (compared regular versus high dose RBZ) was a double-masked, multicenter RCT that evaluated two doses of RBZ (0.5 mg versus 2 mg). The study outcome showed that 2 mg RBZ (high dose) did not show any additional benefits over 0.5 mg dose at the primary endpoint at month 6 (+7.01 in the 2 mg group vs. +9.43 letters in the 0.5 mg group; P = 0.161).
RESTORE: A Twelve-Month Study to Assess the Efficacy and Safety of Ranibizumab (Intravitreal Injections) in Patients with Visual Impairment Due to Diabetic Macular Edema and a 24 month open-label extension study. It was a phase 3 RCT that was designed to compare RBZ with laser therapy. At 12 months, BCVA gain was highest in the RBZ monotherapy arm at the primary endpoint (+6.1 vs. +0.8 letters in the laser arm; P < 0.001).
REVEAL: A phase 3 RCT comparing Ranibizumab with laser. At the 12-month study endpoint, RBZ monotherapy was superior to laser since there was a gain of +5.9 letters in the Ranibizumab monotherapy arm vs. +1.4 letters in the laser arm; P < 0.001. In addition, RESTORE and REVEAL studies showed that combining Ranibizumab with laser did not improve the BCVA.
LUCIDATE: Lucentis (Ranibizumab) in Diabetic Macular Oedema: Compared macular laser with Ranibizumab or combination in DME. This study further showed that in addition to improvements in BCVA and CMT, treatment of patients with center involving DME with monthly Ranibizumab was associated with an improvement in contrast threshold, retinal sensitivity on microperimetry amplitudes, and implicit times on electrophysiology.
With the use of several studies, the DRCR network answered questions relating to the effectiveness and timing of intravitreal pharmacotherapy use, combination therapy, and retinal laser photocoagulation to treat DR and DME. An example of such a study is Protocol T.
PROTOCOL-T of DRCR.net: Compared Ranibizumab, Bevacizumab and Aflibercept in DME. While the FDA had approved Ranibizumab and Aflibercept, the use of Bevacizumab was off-label. The study results revealed improvement in vision from baseline to one year with all three drugs. Improvement was most significant with Aflibercept (+13 letters) than Ranibizumab (+11 letters) or Bevacizumab (+10 letters), a statistically significant mean difference of 2-3 letters at one year. This difference appeared to be driven by baseline vision. Half of the

Variation between clinical trials and real-world outcome using intravitreal injection of pharmacotherapy
There has been a universal observation of divergence between the outcomes obtained from the use of intravitreal anti-VEGF in the real world and outcomes reported in randomized clinical trials. The visual outcomes and gains in vision observed have been much poorer. This finding has led to investigations into the reason for this difference. Some possible explanations for this observation include that participants are pre-selected using strict selection criteria and are well ahead motivated to complete the treatment schedule in clinical trials. This is not the case in real life, in which the patients have to grapple with significant challenges ranging from financial to demands on time and often have to deal with other comorbidities. These challenges could be of considerable impact on patients from low socio-economic backgrounds. It has also been shown that undertreatment is a common feature in real-world experience and that most patients do not receive the recommended number of intravitreal anti-VEGF. This real-life experience results in a mismatch between real-world visual outcomes and those of major clinical trials. The frequent clinic visits and treatment burden contributes to this discrepancy. To resolve this challenge, a host of pharmaceuticals with extended durability are at different stages of development. Hopefully, some extended durability options may make it to the bedside soon. Some of the extended durability options in the pipeline include intravitreal injections such as Faricimab, OPT-302, and KSI-301. There are implantable devices such as the Port delivery system (PDS) and Vorolanib. Gene therapy options include RGX-314, and ADVM-022. These therapeutics are currently being investigated for AMD, but could apply to DME if approved. It is expected that any therapy that will join the list of already available anti-VEGFs will be required to have the same or better safety data if compared with already available drugs.

Newer and emerging concepts in DME
The burden of DME and its impact on vision begs for more efficient care and better outcomes for treatment. This situation has fueled the drive for new concepts in understanding the disease process and alternative treatment.
Some of the new concepts in the understanding of DR and DME include in genetic studies, which aim to understand the variable risk diabetes poses to each person living with the disease. This risk may be affected by the individual's genetic make-up. Also, the role of epigenetics may be an essential factor in determining the response to treatment. Screening for DR and DME will take on a newer feel by introducing artificial intelligence algorithms and software, combined with the advantages of teleophthalmology. This will open up access to more persons who can benefit from screening, including persons in more remote places with limited health and eye care. Home OCT for monitoring of DME will provide information into the clinical evolution of DR and DME and answers to what happens to the eye when patients cannot attend the regular clinics. Home OCT will be an added benefit in reducing the burden of attendance to regular clinics to monitor anti-VEGF therapy. The desire for a reduction in clinic visits is a critical need.
The quest to explore alternative pathogenetic pathways outside the anti-VEGF pathway has resulted in the current progress investigating the Ang-Tie pathways and the Kallikrein pathways. In addition, pharmacotherapies are being developed based on these newer principles.
More innovation will be seen as the years unfold and will significantly benefit treatment outcomes, individualizing DME treatment, and patient satisfaction.

Conclusion
It is expected that the number of people living with diabetes will continue increasing, resulting in more patients diagnosed with DR and DME. There is a need to develop more efficient health systems providing holistic care for patients living with diabetes. These systems should provide for the visual needs and consider the psychological and other health needs. Medicare for such patients should ideally be with reduced treatment burden compared to the current situation and preferably fewer hospital visits.
If we succeed in creating these systems, it will positively affect the patients living with diabetes and the society. This will increase the productivity of our DR and DME patients, who then can live a happier and more fulfilling life. pharmacokinetics of the port delivery system with ranibizumab in participants with diabetic macular edema compared with intravitreal ranibizumab (PAGODA). clinicaltrials.gov/ct2/show/ NCT04108156. Accessed June 9, 2021.
[141] ClinicalTrials.gov. A multicenter, randomized study in participants with diabetic retinopathy without centerinvolved diabetic macular edema to evaluate the efficacy, safety, and pharmacokinetics of ranibizumab delivered via the port delivery system relative to the comparator arm (PAVILION). clinicaltrials.gov/ct2/show/ NCT04503551. Accessed June 9, 2021