Diabetic Macular Edema

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Article initiated by:
Cris Martin P. Jacoba, MD, Margalit G. Mitzner, Neelakshi Bhagat, MD, FACS, Marco Attilio Zarbin, MD, PhD, FACS, Jerry Cavallerano, OD, PhD, Paolo A. Silva, MD, Lloyd P. Aiello, MD, PhD, Mohamed A. Elmasry, MD, PhD
All contributors:
Theodore Leng, MD, MS, Koushik Tripathy, MD (AIIMS), Neelakshi Bhagat, MD, FACS, Jennifer I Lim MD, Cris Martin P. Jacoba, MD, David Kitchen, Galin J. Spicer, MD MBA
Assigned editor:
Neelakshi Bhagat, MD, FACS
Review:
Assigned status Up to Date
 by Neelakshi Bhagat, MD, FACS on December 12, 2024.


Sponsored in part by Boehringer Ingelheim International GmbH

Disease Definition

Diabetic macular edema (DME) is the accumulation of excess fluid in the extracellular space within the retina in the macular area, typically in the inner nuclear, outer plexiform, Henle’s fiber layer, and subretinal space.[1][2]

Pathophysiology

Figure 1: Diabetic macular edema. A: Schematic diagram of DME. Microaneurysms or damaged capillaries resulting from the breakdown of the blood-retina barrier leak fluid to the extracellular space, resulting in a swollen retina. Resorption of DME is dependent on the adjacent capillaries and retinal pigment epithelium. Resorption of fluid may leave behind lipoprotein residues seen as exudates. B: Optical Coherence Tomography image of DME. Published online with permission from the AAO.

Chronic hyperglycemia-related accumulation of advanced glycated end products (AGEs) disrupts the blood retinal barrier (BRB) characterized by endothelial cell junction breakdown and pericyte loss. The inner BRB is composed of endothelial cells in the retinal capillaries, while the outer BRB is composed of retinal pigment epithelium (RPE) cells. Altered BRB leads to interstitial fluid accumulation within and underneath the retina through leakage of molecules dependent on intact cell to cell junctions (Figure 1).[3] Evidence also shows that DME has an inflammatory component to the disease, with several chemokines and cytokines involved in its development. These factors include vascular endothelial growth factor (VEGF), interleukins (ILs), matrix metalloproteinases (MMPs), and tumor necrosis factor (TNF). Upregulation of multiple pathways leads to increased inflammation, oxidative stress, and vascular dysfunction.[4] There are also significant changes in the neurovascular unit, altering the homeostasis between astrocytes, ganglion cells, Müller cells, retinal vascular endothelial cells, and amacrine cells.[5] Retinal vascular permeability changes also involve the kallikrein-kinin system, which induces vasorelaxation via bradykinin and nitric oxide.[6][7][8]

Natural History

DME can develop at any stage of diabetic retinopathy (DR), from mild nonproliferative diabetic retinopathy (NPDR) to proliferative diabetic retinopathy (PDR), but is more frequent as the severity of DR increases. DME threatening or at the fovea is more likely to result in blurred vision and metamorphopsia. When the DME involves or threatens the fovea, the risk of moderate visual loss (MVL, defined as a three-line or more decrease of visual acuity, equivalent to a doubling of the visual angle) over 3 years in the Early Treatment of Diabetic Retinopathy Study (ETDRS) was 24% without treatment.[9] The disease course is variable, with some eyes having chronic persistent DME spanning several years, while other eyes have rapid spontaneous resolution, although the risk of recurrence is always present.

Prevalence

The Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR) found that DME incidence over 25 years among people with type 1 DM (T1DM) was 29%.[10] The Diabetes Control and Complications Trial (DCCT) reported that 27% of people with T1DM had DME within 9 years of onset of diabetes.[11] For people with type 2 DM (T2DM), the WESDR found that 25.4% of those who used insulin and 13.9% of those who did not use insulin had DME.[10] Yau et al. estimated the global prevalence of DME at 6.8% among people with DM. Estimates in the United States are between 2.7% to 3.8%, with non-Hispanic whites less likely to have DME versus non-Hispanic blacks.[12][13][14]

Figure 2: Circinate exudates. A: Blue arrows - Circinate exudates, defined as exudates arranged in a circular appearance. B: OCT b-scan across the fovea confirming the presence of DME associated with an elevated foveal contour. The patient’s best-corrected vision was 20/32.

Risk Factors

Risk factors for DME and DR are similar. These risks include a longer duration of diabetes mellitus (DM), poor control of DM with elevated hemoglobin A1c (HbA1c), hypertension, and hyperlipidemia. Other secondary risk factors include impaired renal function and the use of thiazolidinediones.[15][16][17]

Prevention

Primary prevention of DME involves intensive control of DM, blood glucose, hypertension, blood lipids, and other systemic risk factors. The Diabetic Retinopathy Clinical Research (DRCR) Protocol W investigated whether aflibercept injections in eyes with baseline moderate to severe NPDR could prevent the eventual development of center-involved DME (ci-DME) with vision loss.[18] Vision loss was defined as a 10 letter or more decrease in visual acuity (VA) at 1 visit, or a 5 to 9 letter decrease at 2 consecutive visits, with the decrease in vision attributed to the ci-DME. The 2-year cumulative probability of developing ci-DME with vision loss was 14.8% in the sham group versus 4.1% in the aflibercept group. However, there was no significant difference in mean change of visual acuity (VA) between both groups. From baseline to the 2-year checkup, eyes treated with sham had a mean (SD) change of -2.0 (6.1) letters, while aflibercept treated eyes had a -0.9 (5.8) letter change (adjusted mean difference 0.5 letters, [97.5% CI: -1.0 to 1.9 letters, p=0.47]. At present, the use of anti-VEGF injections for the prevention of ci-DME is still not the standard of care.

Diagnosis

History

DME is suspected in patients with any level of DR who present with blurred vision or metamorphopsias. A detailed history including the approximate date of onset of diabetes, the use of insulin versus oral antihyperglycemic agents, and the quality of metabolic control (e.g., HbA1c level) should be elicited. Any associated medical problems such as hypertension, hypercholesterolemia, renal disease, and thyroid disease should be identified, along with a thorough review of medications. It should be noted that mild to extensive DME may be present without symptoms evident to the patient.

Figure 3: Dense macular exudates involving the fovea. A: Blue arrow– Dense foveal exudates. B: Red arrow– OCT b-scan across the fovea confirming the presence of DME and the dense foveal exudate. The patient’s best-corrected vision was 20/200.

Physical Examination

Patients undergo a detailed biomicroscopic examination using the slit lamp biomicroscope and indirect ophthalmoscope. Historically, DME classifications were based on the ETDRS definitions of clinically significant macular edema (CSME). The specific criteria for diagnosing CSME were:

  1. Retinal thickening at or within 500 μm of the center of the fovea
  2. Hard exudates at or within 500 μm of the center of the fovea if adjacent to an area of retinal thickening
  3. Retinal thickening of at least 1 disc area any portion of which is within 1500 μm (approximately 1 disc diameter) from the center of the fovea


Thus, CSME as defined by the ETDRS in the 1980s is a clinical diagnosis made by slit-lamp examination using a contact lens. While clinical examinations remain essential for the full evaluation of DME, Optical Coherence Tomography (OCT) is now routinely used to complement physical examination in the diagnosis of DME. The management of DME is currently based on the central subfoveal thickness (CST) on the macular OCT.

Signs

Macular thickening with or without hard exudates may be seen with stereo biomicroscopy. However, some eyes may present without apparent signs of retinal thickening on clinical examination despite significant DME as observed using OCT. Thickening can occur in various patterns: focal, multifocal, and diffuse areas of retina thickening. Despite these terms being frequently used, there are no well-established standard definitions, and different authors use them inconsistently.[19] In the ETDRS, focal leakage results from microaneurysms that may be treated with fluorescein angiography (FA) guided focal laser, while diffuse capillary leakage is from a more widespread breakdown of the BRB, which may be treated with grid laser.[20] Hard exudates in various patterns may also be seen, including circinate rings and focal aggregations of exudates (Figures 2-3). Hard exudates consist of lipoprotein residues of serous leakage from damaged vessels, serving as biomarkers for DME.

Figure 4: Basic structural changes seen in OCT with DME. Yellow bracket– Generalized retinal swelling. Blue arrow– Cystoid macular edema. Red arrow– Subretinal fluid.

Symptoms

DME may present with decreased visual acuity (VA), metamorphopsia, changes in color perception, and difficulty reading, although it may also present asymptomatically.

Vision and DME

Studies show a poor to modest correlation between visual acuity and central subfoveal thickness (CST) on OCT, within the range of 0.3-0.5.[21][22] Over two years, only around 12-14% of the change in VA can be attributed to the change in OCT thickness for eyes with DME. In a study by the DRCR Network, the slope of the best fit line shows an approximately 4.4 letter improvement (95% CI: 3.5, 5.3) for every 100-micron decrease in CST at baseline.[22] Interestingly, on follow-up after treatment with macular laser photocoagulation, there were some eyes with paradoxical improvement in VA with increased CST (7-17% at different time points) and paradoxical worsening of VA with decreased CST (18-26% at different time points). These findings highlight how OCT measurements cannot be used as a perfect surrogate for visual acuity; however, in clinical and research settings, the technology remains an important tool. The DRCR has recommended a 10% change in CST to indicate a real change that can be considered in clinical decision-making.

Diagnostic Procedures

1. Optical Coherence Tomography (OCT)

Figure 5: Montage of center-involved versus non-center involved DME. Top Row A: Non-center involved DME. Retinal thickening does not involve the central 1-mm subfield zone (innermost circle) per the en-face OCT heatmap, as seen on b-scan. Bottom Row B: Center-involved DME. Retinal thickening involves the central 1-mm subfield zone (innermost circle) per the en-face OCT heatmap and b-scan. Published online with permission from the AAO.

OCT within recent years has quickly become an important ancillary procedure in the diagnosis and treatment of DME. Three basic structural changes can be seen: retinal swelling, cystoid macular edema, and subretinal fluid (Figure 4). Macular scans can quickly and accurately identify even subtle areas of thickening, along with quantitative metrics for different areas. Changes in the anatomic distribution of DME can be monitored over time, especially the fluid’s relationship to the fovea. This information has proven crucial regarding clinical and research implications for the evaluation and management of DME. More recently, the International Council of Ophthalmology (ICO) guidelines for diabetic eye care in 2018 have adopted the clinical entity of center-involved DME (ci-DME) versus non-center involved DME (non-ciDME) for the evaluation of macular fluid (Figure 5). The classification is:

  1. Center-involved DME: Retinal thickening in the macula that involves the central subfield zone (1 mm in diameter)
  2. Non-center involved DME: Retinal thickening in the macula that does not involve the central subfield zone (1 mm in diameter)


Aside from the location of the swelling, the DRCR retina network has given recommendations on CST treatment thresholds based on sex-matched standards.[23] The thresholds were different per OCT machine since thickness measurements cannot be compared between different devices, with each device having its own normative database and algorithms. In DRCR Protocol T, in conjunction with visual acuity, treatment eligibility thresholds per machine were:

  1. Heidelberg Spectralis - 320 μm for men or 305 μm for women
  2. Zeiss Cirrus OCT - 305 μm for men or 290 μm for women
  3. Zeiss Stratus OCT - 250 μm for both men and women


Moreover, OCT is a more sensitive method for objective evaluation of vitreomacular interface abnormalities (VMIA), which include vitreomacular adhesion (VMA), vitreomacular traction (VMT), and epiretinal membrane (ERM). Identifying VMIA is crucial when diagnosing the etiology of macular edema, whether it is primarily from DME, from secondary causes of VMIA, or combined mechanism macular edema.

Figure 6: Disorganization of the retinal inner layers. OCT images showing combinations of presence or absence of DRIL and DME. The central 1-mm area is enclosed in the box. Upper images show segmentation of inner retinal layers, with the white lines demarcating the boundaries between IPL-INL and the INL-OPL. Image credit to: Barham et al., Association of Macular Nonperfusion, Leakage, and DRIL (ARVO poster, 2016)

OCT Biomarkers for DME

DME's different OCT features have been associated with disparate prognostic outcomes and treatment responses.

  1. Disorganization of the retinal inner layers (DRIL) is thought to represent damaged cells within the inner retinal layers, indicating a disruption in the normal visual pathway from the photoreceptors to the ganglion cells.[24] DRIL is identified on OCT when there is disruption of the demarcating interface lines between the ganglion cell-inner plexiform complex (GCL-IPL), inner nuclear layer (INL), outer plexiform layer (OPL), and outer nuclear layer (ONL). Eyes with DRIL have a worse baseline and final VA despite anti-Vascular Endothelial Growth Factor (VEGF) injections and have almost eight times greater risk for poor visual recovery. In contrast, the resolution of DRIL has resulted in better visual outcomes (Figure 6).[25][26][27] DRIL was better correlated to VA when compared to glycemic status and CST.[24]
  2. External limiting membrane (ELM) and ellipsoid zone (EZ) disruption strongly correlate with baseline and final BCVA. At the same time, restoration of the EZ was a requirement for good visual recovery in some studies (Figure 7).[28][29][30][31][32] The ELM connects a row of zonular adherents to the photoreceptor cell bodies, while the EZ represents the isthmus between the outer and inner segments of photoreceptors.[33]
  3. DME associated with vitreomacular interface abnormalities (VMIA), notably ERM and VMT, has poorer visual outcomes (Figure 8).[34][35] VMIA have been observed in 7%-16% of eyes with DME, with an annual incidence of up to 4.5%.[36][37] For VMA, the READ-3 trial showed that eyes with VMA still had a good response to anti-VEGF therapy.[38] Presence of posterior vitreous detachment (PVD) has been associated with improved visual outcomes. Nasrallah et al. reported that DME was present in 55% of eyes with an attached hyaloid, compared to only 20% of eyes with PVD.[39] Hikishi et al. reported only a 25% rate of spontaneous resolution in eyes with attached posterior hyaloid, compared to a 55% resolution rate in eyes with PVD.[40] The role of the vitreous and VMIA concerning DME, which may be related to changes in transvitreal oxygenation, hyalocyte proliferation from vitreous remnants on the ILM, and the present growth factors in the premacular hyaloid, is still being investigated.[41][42][43][44]
    Figure 7: External limiting membrane and ellipsoid zone disruption. A: DME with large cystic spaces (blue arrow) and exudates (green arrows). Despite anti-VEGF treatment, DME persisted. The EZ and ELM were still intact, with BCVA of 20/32. B: Five years after photo A, extensive ELM and EZ disruption (red bracket) developed which involved the fovea. A few chronic parafoveal cysts can still be seen. BCVA dropped to 20/63.

2. Fluorescein Angiography

Figure 8: Epiretinal membrane associated with DME. Dense epiretinal membrane overlying the retinal surface, with an elevated foveal contour and significant intraretinal cystic spaces in a patient with diabetes. Published online with permission from the AAO.
Figure 9: Focal and diffuse DME. A and B: Fundus photo showing circinate exudates, with adjacent microaneurysms and leakage seen on FA. C and D: Fundus photo with subtle signs of macular thickening, with diffuse, poorly demarcated capillary leakage seen on FA. Published online with permission from the AAO.

Fluorescein angiography (FA) is performed to identify leaking microaneurysms or capillaries to guide laser treatment, and areas of retinal ischemia. Leakage on the angiogram is not synonymous with retinal edema. Focal DME is characterized by focal leakage from microaneurysms or capillaries. In contrast, diffuse DME is diagnosed when poorly demarcated areas of capillary leakage are present (Figure 9). Recently, there has been a decreasing trend in the use of FA in the management of DME, likely due to the procedure being more invasive and time-consuming compared to OCT.[45] Contraindications to the use of FA include pregnancy and allergy associated with the contrast dye.

Laboratory Testing

Primary: HbA1c (Glycated Hemoglobin), Blood pressure, Lipid Profile.  Secondary: Hemoglobin (anemia exacerbates diabetic retinopathy and may be associated with diabetic nephropathy), Fasting Blood Sugar (FBS), Post Prandial Blood Sugar (PPBS), Urea, Creatinine, Urine microalbumin levels, Thyroid panel.

Differential Diagnosis

Figure 10: Pseudophakic cystoid macular edema/Irvine-Gass Syndrome. A: Color fundus photograph of an optic nerve head and macula 3 months after complex cataract surgery. A small incidental grayish-yellow adult vitelliform dystrophy lesion is present in the subfoveal region (circled). B: A mid-phase fluorescein angiography image demonstrates cystic hyperfluorescence, with a classic petaloid pattern. As is typical in eyes with pseudophakic CME, there is mild hyperfluorescence of the nasal portion of the optic nerve head. C: OCT shows cystic retinal thickening and a subfoveal vitelliform lesion. D: Following 8 weeks of topical steroidal and nonsteroidal anti-inflammatory therapy, OCT shows that the CME has fully resolved. Published online with permission from the AAO.

Other causes of macular edema include retinal vein occlusion, ruptured macroaneurysm, Irvine-Gass syndrome, radiation retinopathy, hypertensive retinopathy, subfoveal choroidal neovascularization, retinal vein occlusion, and VMIA. OCT and FA ancillary diagnostics can help differentiate between these differential diagnoses (Figures 10-11).

Figure 11: Vitreo-macular traction with secondary macular edema. A: Color fundus photograph of the right eye with pseudohole and epiretinal membrane with tractional macular edema. B: Optical coherence tomography image of same patient showing vitreomacular traction, epiretinal membrane, and resulting macular edema. C: Optical coherence tomography of the same eye after vitrectomy surgery with epiretinal membrane peeling. Published online with permission from the AAO.

Management

Medical therapy

  • Strict control of diabetes, blood glucose, hypertension, and hypercholesterolemia[46]
  • Diet Modification
  • Weight Loss
  • Exercise

Pharmacotherapy

At present, anti-VEGF agents are the first-line treatment for DME requiring treatment. Since 2005, intravitreal bevacizumab has been used off-label for ocular conditions. FDA approved ranibizumab for DME in 2012, Aflibercept in 2014 and Brolucizumab and Faricimab in 2022.  

DRCR Retina Network anti-VEGF treatment algorithm

Six monthly injections are given unless VA is 20/20 or better, and CST is <320μm for men or <305μm for women on the Heidelberg Spectralis, in which case treatment may be withheld starting the 4th month. At the 6th monthly visit, if stability is achieved in vision or CST from the previous 2 or more visits, or DME has resolved, further treatment may be withheld. Stability is defined as:

  1. Lack of improvement
    • No BCVA increase of ≥5 letters (approximately 1 line on a Snellen chart)
    • No decrease in OCT CST ≥10%
  2. No worsening
    • BCVA decreases ≥5 letters (approximately 1 line on a Snellen chart) in the setting of persistent DME
    • OCT CST increases ≥10%


If there is worsening on follow-up, anti-VEGF injections are resumed. In general, eyes showing stability may be followed-up in 3-4 months, and sooner as needed. Withholding injections does not require 20/20 vision or a dry macula, only evidence of stability over the previous 2 or more visits. DRCR Protocol I published the first anti-VEGF PRN treatment algorithm for DME. Long-term data show that even without using a monthly treatment protocol, eyes with persistent DME often maintain good BCVA over the long term in clinical trial settings.[47] Outside of trial settings, the five-year extension study of Protocol I showed that CST remained stable among eyes given anti-VEGF; however, mean BCVA worsened between the 5th and 2nd-year time points.[48] On average, patients are given 6-8 injections in the first year, 2-4 injections in the second year, and 0-1 injections beginning the third year.[49]

Clinical considerations in the anti-VEGF treatment of DME

Observation is recommended for eyes with ci-DME and visual acuity of 20/25 or better. This recommendation is based on the findings of DRCR Protocol V, where patients were randomized to receive either aflibercept injections, macular laser, or observation. At the 2-year endpoint, the mean BCVA was 20/20, and the rates of ≥ 5 letter vision loss (16-19%) were similar among all three groups. Given the risks of ocular infection and the costs associated with intravitreal injections, observation is a viable treatment option in these patients if they can reliably follow up and receive appropriate therapy when there is clinical deterioration. In contrast, among eyes with ci-DME presenting with 20/50 vision or worse, Protocol T results showed that aflibercept was superior to both ranibizumab and bevacizumab, with area under the curve analysis showing better visual outcomes over 1 year.[50] However, the superiority of aflibercept over ranibizumab was not maintained at the 2-year checkup.[23] Bevacizumab thinned the retina the least; however, all 3 medications had similar visual outcomes among eyes with baseline vision of 20/40 or better.

Not all treatment results in complete resolution of DME, with 40% of eyes still showing persistent DME (defined as never having a CST < 250μm through 6 months on time-domain OCT) in Protocol I over 2 years.[47] Eyes given bevacizumab were more likely to have persistent DME than eyes given aflibercept. The percentage of eyes with complete resolution increases with each ranibizumab or aflibercept injection.[51] At the 3-year follow-up, eyes with chronic persistent DME still had a significant 7 letter mean improvement compared to baseline, lower than the 13 letter mean improvement in eyes with complete DME resolution.[52] Importantly, only 3.4% of eyes with chronic persistent DME lost ≥ 2 lines of vision over 2 years regardless of the type of anti-VEGF they received.[53] To summarize, in clinical trial settings, a substantial proportion of eyes with persistent DME still have ≥ 2 lines of improvement in vision over the long term, with very few eyes developing considerable vision loss.

For eyes that do not respond optimally, switching to another anti-VEGF drug is a treatment option. The switch is typically from bevacizumab to either ranibizumab or aflibercept, or ranibizumab to aflibercept. The rationale for switching is that aflibercept has 100 times more affinity to VEGF-A than bevacizumab or ranibizumab, while concurrently binding placental growth factor (PIGF) and VEGF-B.[54] Aflibercept also has a longer half-life and can negate more cytokines that promote DME development. Most studies looking at switching are retrospective and show a significant reduction in CST; however, visual outcomes vary.[55][56][57][58][59][60][61][62][63][64][65][66][67][68] Some eyes may be delayed responders to anti-VEGF. These eyes need more than the initial 3-6 monthly injections to show significant improvement but eventually catch up with immediate responders.[69][70] It may be viable to continue treatment with the same medication if there is at least a trend of continued improvement, as bevacizumab and ranibizumab are more cost-effective options. Caution is warranted for switching, as any clinical improvement may be due to continued treatment among delayed responders instead of the shift in medications.

DRCR protocol AC was a randomized controlled trial evaluating the relative efficacy of administering aflibercept monotherapy compared with bevacizumab first with a switch to aflibercept (step therapy) in eyes with suboptimal response despite treatment. A total of 312 eyes with moderate vision loss from ci-DME were enrolled. Over a 2-year period, the mean improvement in VA was 14.0 letters in the bevacizumab-first group and 15.0 letters in the aflibercept-monotherapy group (adjusted difference, 0.8 letters; 95% confidence interval, −0.9 to 2.5; P=0.37). At 2 years, the mean changes in VA and retinal CST were similar in the two groups.[71]

Steroids

Intravitreal steroids improve vision and decrease retinal thickness, as there is an inflammatory component to DME. Steroids have powerful anti-edematous and anti-inflammatory effects as they decrease several pro-inflammatory mediators (IL-6, IL-8, TNF-α, MCP-1, ICAM-1, VEGF, etc).[72] However, long-term results have not shown maintenance of initial clinical improvement. In DRCR Protocol I, although the group given intravitreal triamcinolone had a similar response with ranibizumab in the first 6 months, vision declined due to cataracts. Even with cataract surgery, the final vision did not recover to the levels comparable to the group given ranibizumab.[47] In Protocol U eyes with persistent DME despite at least 6 ranibizumab injections were randomized to continue ranibizumab monotherapy, or shift to ranibizumab plus dexamethasone (Ozurdex).[73] At 6 months average visual gain was similar in both groups, although the improvement in CST was greater in the combination group. Phakic eyes given intravitreal steroids often develop cataracts needing surgery, and are at risk for intraocular pressure (IOP) elevations leading to glaucoma.

Pharmacotherapy Landmark Studies

Anti-VEGF

  • Bevacizumab: Bevacizumab is a recombinant humanized monoclonal IgG1 antibody that binds VEGF. Bevacizumab is given off-label for the treatment of DME, and remains the most cost-effective treatment option among anti-VEGF medications.[74] In the BOLT study, intravitreal Bevacizumab (1.25 mg) at 6-week intervals was reported to be more effective than modified ETDRS focal/grid laser in terms of improvement in visual acuity at 12 months.[75] In DRCR Protocol T, a comparison between bevacizumab, ranibizumab, and aflibercept, 1-year results showed that bevacizumab thinned the retina the least.[23] However, all 3 medications had similar visual outcomes among eyes with baseline vision of 20/40 or better.[53] Intravitreal bevacizumab doses of 1.25 to 2.5mg have shown improvement in best-corrected visual acuity and reduced macular thickness on OCT at 24 months in The Pan-American Collaborative Retina Study Group.[76]
  • Ranibizumab: Ranibizumab is a recombinant humanized IgG1 monoclonal antibody fragment that binds and inhibits VEGF-A.[77] It is FDA approved for the treatment of DME.
    1. DRCR Protocol I was the first definitive phase III study demonstrating the effectiveness of ranibizumab for DME treatment.[47] Four treatment arms were compared: ranibizumab with immediate grid/focal laser, ranibizumab with macular laser given only for at least 6 months of persistent DME, intravitreal triamcinolone with immediate macular laser, and macular laser with sham injections. Results showed that ranibizumab in an as-needed treatment protocol was superior to laser therapy. Eyes treated with ranibizumab gained an average of 8-9 letters, versus an average of only 3 letters gained with laser therapy at the 1-year endpoint. Protocol I revolutionized the treatment protocol for DME when it was published in 2011. Before this study, macular laser was considered the 1st line therapy for DME, a treatment protocol originating from the original ETDRS papers first published in 1985.
    2. RISE and RIDE - The two-year results for ranibizumab in DME showed that 98% of patients maintained vision (lost less than 15 letters) with 0.3mg monthly injections, 34-45% of patients gained at least 15 letters, and mean visual acuity gain was 10.9 to 12.5 letters.[78] Only 45-49% of patients needed macular laser compared with 91-94% in the control group. No additional benefit was seen with 0.5mg monthly versus 0.3mg ranibizumab monthly.[79]
  • Aflibercept: Aflibercept is a soluble decoy receptor that binds VEGF-A, VEGF-B, and placental growth factor with high affinity.[79] It is termed a decoy receptor or a “VEGF-trap” as VEGF mistakenly binds with aflibercept instead of the body’s native receptors, reducing VEGF’s activity. It is FDA approved for the treatment of DME. In the Da Vinci study, DME patients were assigned randomly to 1 of 5 treatment regimens: Aflibercept 0.5mg every 4 weeks (0.5q4); 2mg every 4 weeks (2q4); 2mg every 8 weeks after 3 initial monthly doses (2q8); or 2mg dosing as needed after 3 initial monthly doses (2prn), or macular laser photocoagulation.[80] Mean improvements in BCVA in the aflibercept groups at week 52 were 11.0, 13.1, 9.7, and 12.0 letters for 0.5q4, 2q4, 2q8, and 2prn regimens, respectively, versus -1.3 letters for the laser group. The proportion of eyes with gains in BCVA of 15 or more ETDRS letters at week 52 in the aflibercept groups were 40.9%, 45.5%, 23.8%, and 42.2% versus 11.4% for laser. Mean reductions in CST in the aflibercept groups at week 52 were -165.4μm, -227.4μm, -187.8μm, and -180.3μm versus -58.4μm for laser.[79] The PHOTON trial evaluated the use of high-dose 8mg aflibercept every 12 (8q12) or 16 (8q16) weeks, compared with conventional dosing of 2mg every 8 weeks.[81] Results showed that the 8mg extended interval dosage was non-inferior to conventional treatment when comparing gains in BCVA and retinal thinning at 48 weeks. There was an increase of 9.2, 8.8, and 7.9 letters, and a mean CST reduction of -165μm, -172μm, and -148μm, for the 2q8, 8q12, and 8q16 groups at 48 weeks, respectively. Patients in the high-dose group with a 50μm increase in CST or a 10-letter loss from week 12 onwards had their dosing schedule shortened to either 12 or 8 weeks, but 93% of patients remained on dosing intervals of 12 weeks or more. There was no increase in hypertension in the high-dose group.
  • Faricimab: Faricimab is a novel combined mechanism inhibitor that binds both Angiopoietin-2 (Ang-2) and VEGF-A with high specificity and affinity. The 1-year results from the phase II BOULEVARD study show that in patients given the 6.0mg dose, there was a statistically significant gain of 3.6 letters over ranibizumab.[82] Moreover, faricimab showed improvement in DR severity, reduced CST, and had a longer time to retreatment than ranibizumab. There were no unexpected safety concerns noted. The phase III YOSEMITE and RHINE non-inferiority trials compared faricimab with aflibercept in patients with DME.[83] The non-inferiority primary endpoint of BCVA was achieved with faricimab given every 8 weeks. More than 50% of patients achieved dosing of every 16 weeks, and more than 70% achieved dosing of every 12 weeks or longer. These results demonstrate the potential of faricimab to decrease the treatment burden on patients by extending the intraocular durability of anti-VEGF. FDA approved the use of faricimab for DME as 4 monthly loading doses followed by injections every 1-4 months, or a loading dose of 6 monthly injections followed up with injections every 2 months.
  • Brolucizumab: Brolucizumab is a single-chain antibody fragment with a high affinity for VEGF. Brolucizumab’s low molecular weight of 26kDa allows more of the drug to be delivered intraocularly per injection, with the potential for increased durability and effective tissue penetration in the eye. The phase III KESTREL and KITE 52 week results showed that brolucizumab was non-inferior to aflibercept in the mean improvement of BCVA, more patients had CST <280μm without persistent macular fluid, and >50% of brolucizumab 6mg patients were maintained on q12 weekly dosage after loading.[84] However, reports of retinal vascular occlusion (RVO) and retinal vasculitis (RV) with intraocular inflammation (IOI) have been reported.[85][86] Risk factors for developing these adverse reactions include a prior history of IOI or RVO in the 12 months before brolucizumab initiation, female sex, and same-day bilateral injections.[87][88] FDA approved use of Brolucimab 6 mg for the treatment of DME in June 2022 for an injection every 8-12 weeks after a loading dose of 5 injections 6 weeks apart.

Steroids

  • Triamcinolone (1 mg or 4 mg) preservative-free intravitreal injection was less effective and had more side-effects for most patients with DME than focal/grid photocoagulation at 2-years follow-up (Protocol B).[89]
  • Dexamethasone (Ozurdex) 0.7 mg biodegradable implant improved vision by at least 15 letters in 22% of patients at 3 years in the phase III MEAD study.[90] The FDA approved the 0.7 mg implant for DME, and at this dose, 41.5% of patients needed anti-glaucoma medications, with 0.6% needing glaucoma surgery. Around 60% of eyes in the 0.7 mg implant group had cataract surgery. The implant is effective for approximately 3-6 months intraocularly.
  • Fluocinolone acetonide (Iluvien) 0.19 mg non-biodegradable implant is a sustained release device effective for up to 3 years intraocularly. It is FDA approved to treat DME in patients who have been previously treated with a course of corticosteroids and did not have a clinically significant rise in IOP.[91][92] At the 0.2 μg/day dosage BCVA improvement of at least 15 letters was found in 28.7% of patients, with 38.4% needing anti-glaucoma medications and 4.8% needing glaucoma surgery. The latter figure was reduced to 0% among eyes that did not have a history of IOP elevation with a prior steroid challenge. The implant can have complications like the dexamethasone implant, including cataracts and implant migration.

Laser Photocoagulation

Figure 12: Focal laser for focal CSME. A: Planning of focal laser for focal CSME. Note the identified treatment areas, specifically the leaking-microaneurysms that would be highlighted on FA. B: Focal laser-treated areas with parameters. Published online with permission from the AAO.

Before developing anti-VEGF for DME, the standard treatment for CSME was macular laser photocoagulation since the ETDRS was published in 1985. In “focal” CSME, a focal laser pattern is used to treat leaking microaneurysms identified on the FA that contribute to the retinal edema (Figure 12). In “diffuse” CSME, intraretinal leakage is noted on the FA from dilated retinal capillary beds or intraretinal microvascular abnormalities (IRMA) without isolated, discrete foci of leakage. Macular grid is done for diffuse macular edema (Figure 13). Laser photocoagulation has been shown to decrease the risk of moderate visual loss (loss of 15 or more ETDRS letters) from 24% to 12% by 3 years.[9] After laser treatment, the follow-up examination is at three months. If residual CSME is noted, OCT and FA may be performed to evaluate the benefit and location of repeat laser treatment. With the FDA approval of anti-VEGF for DME, focal/grid laser is only indicated in patients with non-ciDME. Especially in resource-limited countries with decreased access to anti-VEGF agents, macular laser remains a viable treatment option for patients with DME.

Figure 13: Grid laser for diffuse CSME. A: Planning of grid laser for diffuse CSME. Note the identified treatment area, specifically the outlined region with diffuse edema that would be highlighted on FA. B: Grid laser-treated area with parameters. Published online with permission from the AAO.

Combined Therapy

  • Intravitreal ranibizumab with laser: Intravitreal ranibizumab with prompt (within 1 week) or deferred (after 24 weeks) laser is more effective compared to focal/grid laser alone for the treatment of ci-DME (Protocol I).[47] Ranibizumab is injected intravitreally at baseline with prompt laser, followed by monthly ranibizumab injections for 4 months followed by the continuation of injections at 16 weeks if the OCT central subfield thickness is ≥250 um with visual acuity worse than 20/20.
  • Steroid with laser: Intravitreal triamcinolone (IVT, 4 mg) with focal/grid laser within a week is more effective than laser alone at 4 months (Protocol B). However, long-term benefit with this combined therapy was not seen, with mean BCVA better in the laser monotherapy group than the combined therapy group from the 16-month timepoint until the 2-year endpoint. Complications of steroid therapy included cataracts, ocular hypertension, and glaucoma. The difference in BCVA could not be attributed fully to the development of cataracts. In DRCR Protocol I, visual acuity improvement in eyes given IVT with prompt laser were comparable to eyes given ranibizumab at 6 months, but vision declined afterward until the 2-year timepoint.[47][93] Subgroup analysis in pseudophakic eyes given IVT showed visual improvement was significantly better than in phakic eyes, with results comparable to pseudophakic eyes given ranibizumab at the 1 and 2-year time points.
  • Intravitreal ranibizumab with peripheral targeted retinal photocoagulation (TRP): The DAVE study was a phase I/II clinical trial that evaluated if ranibizumab with TRP could reduce the number of required anti-VEGF injections compared to ranibizumab monotherapy.[94] Peripheral TRP was defined as retinal photocoagulation administered outside the macula to areas of retinal capillary nonperfusion identified on widefield FA. The nonperfused hypoxic retina is thought to upregulate hypoxia-inducible factors and cytokines, including VEGF and erythropoietin, with small studies suggesting that TRP can decrease the anti-VEGF treatment burden.[95][96][97][98][99] At the 3-year endpoint, there was no evidence that combined ranibizumab plus TRP reduced treatment burden or improved vision outcomes compared to ranibizumab alone.

Surgery

No well-constructed studies show a definitive benefit of pars plana vitrectomy (PPV) for managing DME. The theoretical basis for PPV as a treatment option comes from reports that it increases vitreous oxygenation in ischemia, leading to decreased VEGF production, and from the observation that DME is less common among eyes with PVD.[100][101][102][103][104][105] Vitreous viscosity also significantly decreases, which may bring about a greater diffusion of pro-inflammatory cytokines away from the macula.[106] Other authors suggest PPV plus internal limiting membrane (ILM) peeling should be attempted, as its removal brings better resolution of the tractional forces at the vitreoretinal interface known to worsen DME. This procedure also prevents proliferating astrocytes from using the ILM as a scaffold which may lead to ERM.[107] In a systematic review looking at PPV for DME, CST was significantly decreased by 102 μm, and a non-significant VA increase of 2 letters was observed.[108] However, the anatomic benefit was not maintained by the 12-month timepoint. A similar meta-analysis looking at PPV plus ILM peeling versus PPV alone showed no significant difference in postoperative vision and macular thickness.[109] DRCR Protocol D, a prospective study of eyes with DME and VMT, found that at 6 months postop, 43% of eyes had a reduction in central subfield thickness to <250 μm.[110] However, the median VA did not change at 6 months. In 38% of eyes the median visual acuity improved by ≥10 letters, and in 22% the median VA decreased by ≥10 letters. Post-hoc analysis of DRCR Protocol I showed that previously vitrectomized eyes given anti-VEGF for ci-DME had no improved clinical outcomes compared to non-vitrectomized eyes.[111]

Treatment Complications

Complications, listed below, may arise from the various treatment modalities. The per-injection risk of developing complications is also listed below, when available.

Intravitreal injections

  • Endophthalmitis (0.019-0.05%)[112][113][114]
  • Intraocular inflammation (0.09-0.4%)[115]
  • Retinal tears/detachment (0.01-0.08%)[116][117][118]
  • Increase in intraocular pressure (For intravitreal steroids, IOP ≥21 mmHg in 45% at 1 month, 20% at 3 months, and 13% of eyes 6 months post-injection.)[119]
  • Cataract (Common after intravitreal steroid injections. By year three, 83% of patients given IVT had cataract surgery.)[120]
  • Subconjunctival hemorrhage (10%)[121]
  • Vitreous hemorrhage

Laser Photocoagulation

  • Subretinal fibrosis
  • Extension of the laser scar into the fovea
  • Choroidal neovascular membrane
  • Paracentral scotoma
  • Decreased visual acuity

PPV

  • Retinal tears and retinal detachment
  • Vitreous hemorrhage
  • Elevated intraocular pressure
  • Endophthalmitis
  • Cataract

Prognosis

Clinical factors associated with better visual outcomes with anti-VEGF treatment include lower hemoglobin A1c, younger age, less severe DR, absence of ERM, quick and consistent CST decreases with anti-VEGF therapy, and absence of prior panretinal photocoagulation (PRP).[122][123] In terms of anatomic outcomes, eyes with hard exudates within the 6mm foveal center had a larger CST decrease at the end of 1 year. The presence of exudates may be a marker of BRB abnormalities typical of DME responsive to anti-VEGF. Eyes that lack exudates may have other underlying mechanisms of retinal thickening, including cystoid degeneration, traction, or ischemia. In contrast, eyes with high baseline CST ≥ 570μm had a significantly higher chance of developing persistent DME despite monthly ranibizumab therapy.[124] In terms of response to macular laser therapy, the ETDRS reported that worse clinical outcomes were associated with higher blood lipid levels, presence of hard exudates, and diffuse edema.[125]

Matsunaga et al. looked at eyes with DME treated with at least 1 dose of anti-VEGF, and then afterward were lost to follow-up (LTFU) for at least 6 months before returning to the clinic.[126] Their vision worsened significantly at the initial return visit to ~20/69 from ~20/52, however at the 3, 6, and 12-month follow-up, and final checkup, their vision recovered and had no significant difference with their baseline vision. OCT CST also showed similar trends. Gao et al. found that 25% of patients with NPDR and DME had no follow-up for at least 1 year after receiving 1 anti-VEGF injection.[127] Factors associated with LTFU included being Hispanic (OR 1.66), American Indian, Pacific Islander, multiple races (OR 2.6), and unknown race (OR 1.59) compared to whites. Lower adjusted gross income and decreasing baseline vision were also factors significantly associated with LTFU.

Some studies have shown increased risks of end stage renal disease in patients with concurrent DME. Assessment of renal function should be strongly encouraged in patients with chronic DME.

Future Directions

Numerous pharmacotherapy trials for DME treatment are underway. The development of a long-acting anti-VEGF that could remain effective in the vitreous for multiple months or years would significantly decrease the treatment burden for patients needing monthly injections. Novel pharmacotherapies based on different mechanisms of action include anti-VEGF designed ankyrin repeat proteins (DARPins), growth factor inhibitors, anti-inflammatory medications, hormone modulators, acetylcholine receptor blockers, IGF-1 receptor blockers, and neuroprotective/antiapoptotic agents.[128] Port delivery systems FDA approved for wet AMD are in development to treat DR and DME.[129] These experimental therapies have the potential to significantly decrease the burden of treatment while restoring vision to DME patients in the coming years ahead.

Teleophthalmology and Artificial intelligence (AI) are being used to develop screening tools for diabetic retinopathy and DME. These modalities can detect the retinal complications of diabetes remotely, and if this technology is placed in the offices of internists and endocrinologists, it may allow for early detection and timely intervention. [130][131]

Further reading

  1. Bhagat N, Grigorian RA, Tutela A, Zarbin MA. Diabetic macular edema: pathogenesis and treatment. 2009 Jan-Feb;54(1):1-32
  2. Diabetic Retinopathy Clinical Research Network Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology June 2010; 117(6):1064-1077.
  3. Early Treatment Diabetic Retinopathy Study: Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study report number 1. Early Treatment Diabetic Retinopathy Study research group. Arch Ophthalmol 103:1796-1806, 1985.
  4. Michaelides M, Kaines A et al A prospective randomized trial of intravitreal bevacizumab or laser therapy in the management of diabetic macular edema (BOLT study) 12 month data. Ophthalmology June 2010; 117(6):1059-1060.
  5. Schachat AP. A new approach to the management of diabetic macular edema. Ophthalmology 2010 June;117(6):1059-1060.

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  76. ↑ Arevalo JF, Sanchez JG, Wu L, et al. Primary intravitreal bevacizumab for diffuse diabetic macular edema: the Pan-American Collaborative Retina Study Group at 24 months. Ophthalmology. 2009;116(8):1488-1497. e1481.
  77. ↑ Krispel C, Rodrigues M, Xin X, et al. Ranibizumab in diabetic macular edema. World journal of diabetes. 2013;4(6):310.
  78. ↑ Nguyen QD, Brown DM, Marcus DM, et al. Ranibizumab for diabetic macular edema: results from 2 phase III randomized trials: RISE and RIDE. Ophthalmology. 2012;119(4):789-801.
  79. ↑ 79.0 79.1 79.2 Sharma YR, Tripathy K, Venkatesh P, et al. Aflibercept: how does it compare with other anti-VEGF drugs. Austin J Clin Ophthalmol. 2014;1(3):8.
  80. ↑ Do DV, Nguyen QD, Boyer D, et al. One-year outcomes of the da Vinci Study of VEGF Trap-Eye in eyes with diabetic macular edema. Ophthalmology. 2012;119(8):1658-1665.
  81. ↑ David M. Brown, on behalf of the PHOTON study investigators. Intravitreal Aflibercept Injection 8mg for DME: 48-Week Results From the Phase 2/3 PHOTON Trial. Presented at the American Academy of Ophthalmology 2022, September 30-October 3, 2022. Website: https://investor.regeneron.com/static-files/da20405e-b843-402e-855b-d824a15dec60. Accessed: November 29, 2022.
  82. ↑ Sahni J, Patel SS, Dugel PU, et al. Simultaneous inhibition of angiopoietin-2 and vascular endothelial growth factor-A with faricimab in diabetic macular edema: BOULEVARD phase 2 randomized trial. Ophthalmology. 2019;126(8):1155-1170.
  83. ↑ Wykoff CC, Abreu F, Adamis AP, et al. Efficacy, durability, and safety of intravitreal faricimab with extended dosing up to every 16 weeks in patients with diabetic macular oedema (YOSEMITE and RHINE): two randomised, double-masked, phase 3 trials. The Lancet. 2022.
  84. ↑ Brown DM, Emanuelli A, Bandello F, et al. KESTREL and KITE: 52-week results from two Phase III pivotal trials of brolucizumab for diabetic macular edema. American Journal of Ophthalmology. 2022.
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  111. ↑ Bressler SB, Melia M, Glassman AR, et al. Ranibizumab plus prompt or deferred laser for diabetic macular edema in eyes with vitrectomy prior to anti-vascular endothelial growth factor therapy. Retina (Philadelphia, Pa.). 2015;35(12):2516.
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  119. ↑ Martidis A, Duker JS, Greenberg PB, et al. Intravitreal triamcinolone for refractory diabetic macular edema. Ophthalmology. 2002;109(5):920-927.
  120. ↑ Network DRCR. Three-year follow-up of a randomized trial comparing focal/grid photocoagulation and intravitreal triamcinolone for diabetic macular edema. Archives of ophthalmology. 2009;127(3):245-251.
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  122. ↑ Bressler SB, Odia I, Maguire MG, et al. Factors associated with visual acuity and central subfield thickness changes when treating diabetic macular edema with anti–vascular endothelial growth factor therapy: an exploratory analysis of the protocol T randomized clinical trial. JAMA ophthalmology. 2019;137(4):382-389.
  123. ↑ Bressler SB, Qin H, Beck RW, et al. Factors associated with changes in visual acuity and central subfield thickness at 1 year after treatment for diabetic macular edema with ranibizumab. Archives of Ophthalmology. 2012;130(9):1153-1161.
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  125. ↑ Chew EY, Klein ML, Ferris FL, et al. Association of elevated serum lipid levels with retinal hard exudate in diabetic retinopathy: Early Treatment Diabetic Retinopathy Study (ETDRS) Report 22. Archives of ophthalmology. 1996;114(9):1079-1084.
  126. ↑ Matsunaga DR, Salabati M, Obeid A, et al. Outcomes of Eyes With Diabetic Macular Edema That Are Lost to Follow-up After Anti–Vascular Endothelial Growth Factor Therapy. American Journal of Ophthalmology. 2022;233:1-7.
  127. ↑ Gao X, Obeid A, Aderman CM, et al. Loss to follow-up after intravitreal anti–vascular endothelial growth factor injections in patients with diabetic macular edema. Ophthalmology Retina. 2019;3(3):230-236.
  128. ↑ Das A, McGuire PG, Rangasamy S. Diabetic macular edema: pathophysiology and novel therapeutic targets. Ophthalmology. 2015;122(7):1375-1394.
  129. ↑ Holekamp NM, Campochiaro PA, Chang MA, et al. Archway Randomized Phase 3 Trial of the Port Delivery System with Ranibizumab for Neovascular Age-Related Macular Degeneration. Ophthalmology. 2021.
  130. ↑ Kuklinski EJ, Henry RK, Shah M, Zarbin MA, Szirth B, Bhagat N. Screening of Diabetic Retinopathy Using Artificial Intelligence and Tele-Ophthalmology. J Diabetes Sci Technol. 2023 Nov;17(6):1724-1725. doi: 10.1177/19322968231194041. Epub 2023 Aug 29. PMID: 37642475.
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