Early Intervention in Diabetic Macular Edema

Earlier seems to be better in terms of visual acuity improvement in DME.

By Michael A. Singer, MD

The diabetes epidemic continues unabated, and it has become an urgent societal problem requiring global attention. According to a study by the World Health Organization, the international incidence of diabetes increased from 108 million in 1980 to 422 million in 2014.1 Diabetes affects approximately 8% of the population in the United States.2 Diabetic retinopathy (DR) is a leading cause of blindness worldwide, and diabetic macular edema (DME) contributes greatly to this vision loss.3 Therefore, early detection of and prompt intervention in DME are essential in order to preserve vision in diabetic patients. This article reviews treatment options for DME and explains why early intervention is imperative to successful management of these patients.


• Although treatments for DME have shown great promise in clinical trials, the translation of these results into clinical practice remains challenging.

• In clinical trials of anti-VEGF agents, there is a subset of patients who do not achieve the excellent outcomes seen in the overall study population.

• A post hoc study suggests that early response to anti-VEGF treatment may predict long-term response.


All patients with diabetes are at risk of developing DME. The onset of DME is usually insidious and painless. It often does not present until after the disease is advanced and vision loss occurs. Vision loss in DME is a result of vascular exposure to high glucose levels over extended periods of time. Hyperglycemia destroys retinal endothelial cell tight junctions and incites the accumulation of subretinal and intraretinal fluid, leading to the development of macular edema.4

Although DME is reversible in its early stages, chronic edema may lead to irreversible changes in the retina and become debilitating for the patient. If the disease is untreated, 20% to 30% of patients with DME will lose at least 3 lines of vision within 3 years.5 The long-term prognosis for DME is poor, and treatment is recommended immediately, once a patient is diagnosed.6


To initiate prompt intervention, a multidisciplinary approach and novel strategies to detect DME in its early stages are necessary. The American Academy of Ophthalmology recommends annual eye examinations for all diabetic patients to screen for the development of DR and DME.7

The most well-established primary examination technique to diagnose DME is biomicroscopy under stereopsis with high magnification. Optical coherence tomography (OCT) and fluorescein angiography (FA) are also useful as ancillary tests in the evaluation of DME.4 Indeed, OCT is more sensitive in detecting retinal thickening than biomicroscopy, and it provides quantitative information regarding central retinal thickness. FA identifies leaking microaneurysms, and ultra-widefield angiography can now identify areas of retinal ischemia that were not previously appreciated on conventional FA.8

OCT angiography (OCTA) is an emerging imaging modality that can provide novel information in regard to retinal and choroidal vascular diseases. OCTA is a fast, noninvasive tool to examine retinal structures microscopically, and it facilitates the identification of subsequent disorders such as DR and DR-associated complications.9

Improvement of all of these diagnostic techniques in recent years has allowed earlier diagnosis of DME.


Historically, treatment of DME has been based on the definition of clinically significant macular edema (CSME). CSME is defined as (1) retinal thickening within 500 µm of the foveal center; or (2) hard exudates within 500 µm of the foveal center, if associated with thickening of the adjacent retina; or (3) retinal thickening greater than one disc area in size, part of which is within 1 disc diameter of the center of the fovea.4

The primary method of treatment for diabetes-related ophthalmic complications is the management of underlying systemic risk factors, which include intensive glycemic control, blood pressure management, and regulation of lipid levels. However, these methods are often insufficient in controlling DME, in which case more invasive pharmacologic and nonpharmacologic therapy is frequently needed. The EDTRS in 1985 showed the benefit of focal laser for DME (Figure). Focal laser photocoagulation has been considered the standard of care for DME for more than 3 decades. Although laser therapy slows the progression of vision loss in patients with DME, it rarely results in improvement of vision.10 With the advent of intravitreal pharmacologic agents, the prognosis of DME has changed from stabilization to improvement of vision.11

Figure. Changes in the treatment landscape for DME from 1985 to 2016.10

Use of VEGF Inhibitors

Elevated blood glucose leads to a reduction in pericyte function and damage to capillaries, causing retinal hypoxia and ischemia and the activation of inflammatory pathways. The pathogenesis of DME involves upregulated expression of multiple inflammatory cytokines, including VEGF, intercellular adhesion molecule 1 (ICAM-1), interleukin 6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and pigment epithelium–derived factor (PEDF), which promotes vascular permeability and leakage through the blood-retina barrier.12 Anti-VEGF agents directly inhibit the cascade of vascular dysfunction and decrease the risk of worsening DR.13

Several VEGF inhibitors have shown clinical efficacy in the treatment of DME, including ranibizumab (Lucentis, Genentech), bevacizumab (Avastin, Genentech), and aflibercept (Eylea, Regeneron). Two phase 3 prospective randomized controlled trials, RISE and RIDE, demonstrated improvements in visual acuity of 11.7 letters after 2 years in patients with DME who received ranibizumab.14 The BOLT study determined that bevacizumab led to an improvement of 8.6 letters of visual acuity in patients with DME.15 The VIVID and VISTA studies showed improvement in visual acuity of 11.5 letters after 2 years of therapy with aflibercept in patients with DME (Table 1).16

The Diabetic Retinopathy Clinical Research Network (DRCR.net) Protocol I study compared four treatment strategies: (1) focal laser, (2) focal laser plus intravitreal triamcinolone, (3) intravitreal ranibizumab plus prompt focal laser, and (4) intravitreal ranibizumab plus deferred focal laser. The two cohorts of patients treated with ranibizumab in that study experienced greater mean gains in visual acuity and OCT outcomes compared with those receiving laser treatment without ranibizumab.21

Use of Steroids

Intravitreal sustained delivery of steroids, such as with the dexamethasone intravitreal implant 0.7 mg (Ozurdex, Allergan) or the fluocinolone acetonide intravitreal implant 0.19 mg (Iluvien, Alimera Sciences), affects not only VEGF but also other mediators of inflammation.8 In the MEAD study, mean change in best corrected visual acuity (BCVA) from baseline was 3.6 letters with the dexamethasone implant 0.35 mg and 2 letters with sham treatment. The mean number of injections was 4.1 over 3 years.16 The FAME study found improvement of 4.4 letters in patients with low-dose fluocinolone acetonide intravitreal implants and 5.4 letters in those receiving high-dose implants, compared with 1.7 letters in those receiving sham treatment (Table 2).18


The RISE, RIDE, VIVID, and VISTA studies further support the notion that early intervention in DME is crucial to achieving optimal improvement in visual acuity. In these studies, treatment with ranibizumab or aflibercept led to rapid vision improvements, with statistically significant changes observed as early as 7 days after the first injection. Sham- or laser-treated patients who were crossed over to ranibizumab or aflibercept treatment after 24 months achieved smaller visual acuity gains than those who started treatment at the onset of their respective study.16,20


Despite the impressive results achieved in clinical trials of anti-VEGF agents, there is a subset of patients who do not achieve these excellent outcomes. In the RISE, RIDE, VIVID, and VISTA studies, 60% of patients did not achieve a 15-letter improvement in visual acuity. In the DRCR.net Protocol I, 50% of patients did not achieve a 10-letter gain in visual acuity and 26% of patients were nonresponders, defined by a reduction of central subfield thickness on OCT of less than 20%.22

The Early Treatment Diabetic Retinopathy (EARLY) study was performed to determine whether early visual acuity response to anti-VEGF therapy could help to predict who would be a longer-term responder to therapy. This study was a post hoc subset analysis of data from the DRCR.net Protocol I study that examined patterns of improvement in visual acuity in patients who were treated promptly with ranibizumab. The EARLY study found that patients’ responses to therapy could be predicted by as early as 3 months. Mean improvement in BCVA was followed for 3 years, and patients were stratified based on having an excellent response (≥10 letters), an average response (5-9 letters), or a poor response (<5 letters) to treatment with ranibizumab.23 In each group, mean improvements in BCVA through year 3 were within 5 letters of the response seen at week 12 (Table 3).24


Although treatments for DME have shown great promise in clinical trials, the translation of these results into clinical practice remains challenging. Diabetic patients with DME often have higher rates of vascular comorbidities, which result in a significantly higher rate of health care utilization than is seen in those without DME. Patients with DME have an average of 12 additional health care appointments per year compared with diabetic patients with no DME.25 A recent study of compliance trends in patients with DME in the United States demonstrated higher rates of appointment cancellations (10.01%) and no-shows (14.32%) compared with patients with wet age-related macular degeneration.26

A combination of early detection and effective treatment algorithms for DME is needed to reduce the health care burden and improve clinical outcomes for this potentially devastating complication of diabetes.

1. Global Report on Diabetes. World Health Organization. 2016. apps.who.int/iris/bitstream/10665/204871/1/9789241565257_eng.pdf. Accessed September 12, 2017.

2. US Centers for Disease Control and Prevention. County-level estimates of diagnosed diabetes among adults aged ≥ 20 years: Trends 2004-2011. http://slideplayer.com/slide/2778912/. Accessed September 18, 2017.

3. Bhagat N, Grigorian RA, Tutela A, Zarbin MA. Diabetic macular edema: pathogenesis and treatment. Surv Ophthalmol. 2009;54(1):1-32.

4. Zhang X, Zeng H, Bao S, Wang N, Gillies MC. Diabetic macular edema: new concepts in patho-physiology and treatment. Cell Biosci. 2014;4:27.

5. Gangnon R, Davis M, Hubbard L, et al. A severity scale for diabetic macular edema developed from ETDRS data. Invest Ophthalmol Vis Sci. 2008;49(11):5041-5047.

6. Augustin A, Loewenstein A, Kuppermann BD. Macular edema. General pathophysiology. Dev Ophthalmol. 2010;47:10-26.

7. American Academy of Ophthalmology Retina Panel. Preferred Practice Pattern Guidelines. Diabetic retinopathy. San Francisco, CA: American Academy of Ophthalmology; 2012.

8. Park YG, Roh Y. New diagnostic and therapeutic approaches for preventing the progression of diabetic retinopathy. J Diabetes Res. 2016:1753584.

9. Garcia JM, Isaac DL, Avila M. Diabetic retinopathy and OCT angiography: clinical findings and future perspectives. International Journal of Retina and Vitreous. 2017;3:14.

10. [no authors listed]. Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study report number 1. Early Treatment Diabetic Retinopathy Study research group. Arch Ophthalmol. 1985;103(12):1796-1806.

11. Ranchod T, Fine S. Primary treatment of diabetic macular edema. Clin Interv Aging. 2009;4:101-107.

12. Zhang W, Liu H, Al-Shabrawey M, Caldwell RW, Caldwell RB. Inflammation and diabetic retinal microvascular complications. J Cardiovasc Dis Res. 2011;2(2):96-103.

13. Abcouwer SF. Angiogenic factors and cytokines in diabetic retinopathy. J Clin Cell Immunol. 2013;Suppl CID.

14. 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):789-901.

15. Michaelides M, Kaines A, Hamilton RD, 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. 2010;117(6):1078-1086.

16. Brown DM, Schmidt-Erfurth U, Do DV, et al. Intravitreal aflibercept for diabetic macular edema. Ophthalmology. 2015;122(10):2044-2052.

17. Boyer DS, Yoon YH, Belfort R, et al. Three-year, randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with diabetic macular edema. Ophthalmology. 2014;121(10):1904-1914.

18. Campochiaro PA, Brown DM, Pearson A, et al. Long-term benefit of sustained-delivery fluocinolone acetonide vitreous inserts for diabetic macular edema. Ophthalmology. 2011;118(4):626-635.

19. Heier JS, Korobelnik JF, Brown DM, et al. Intravitreal aflibercept for diabetic macular edema: 148-week results from the VISTA and VIVID studies. Ophthalmology. 2016;123(11):2376-2385.

20. Brown DM, Nguyen QD, Marcus DM, et al. Long-term outcomes of ranibizumab therapy for diabetic macular edema: the 36-month results from two phase III trials: RISE and RIDE. Ophthalmology. 2013;120(10):2013-2022.

21. Elman MJ, Aiello LP, Beck RW, et al. Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology. 2010;117(6):1064-1077.

22. 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. Arch Ophthalmol. 2012;130(9):1153-1161.

23. Gonzalez VH, Campbell J, Holekamp NM, et al. Early and long-term responses to anti-vascular endothelial growth factor therapy in diabetic macular edema: analysis of protocol I data. Am J Ophthalmol. 2016;172:72-79.

24. Dugel PU. Can long-term response to anti-VEGF therapy be predicted after three injections in patients with DME? Retina Today. 2016;11(2)78-79.

25. Wallick C, Hansen R, Campbell J, Kiss S, Kowalski J, Sullivan S. Comorbidity and health care resource use among commercially insured non-elderly patients with diabetic macular edema. Ophthalmic Surg Lasers Imaging Retina. 2015;46(7):744-751.

26. Jansen M, Bahadorani S, Singer M, et al. Compliance trends in patients with diabetic macular edema and exudative macular degeneration. Paper presented at: UTHSCSA Ophthalmology Alamo Day; April 8, 2017; San Antonio, TX.w

Sepehr Bahadorani, MD, PhD
• fourth year ophthalmology resident at the University of Texas Health Science Center at San Antonio

Jordan Comstock
• fourth year medical student at the University of Texas School of Medicine at San Antonio

Michael A. Singer, MD
• vitreoretinal surgeon and managing partner at Medical Center Ophthalmology Associates in San Antonio, Texas

No conflicting relationship exists for any author.


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About Retina Today

Retina Today is a publication that delivers the latest research and clinical developments from areas such as medical retina, retinal surgery, vitreous, diabetes, retinal imaging, posterior segment oncology and ocular trauma. Each issue provides insight from well-respected specialists on cutting-edge therapies and surgical techniques that are currently in use and on the horizon.