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Current Insight Into Retinal Disease Management: Focus on DME and Intravitreal Corticosteroids

By: Allen C. Ho, MD, Moderator; Michael D. Ober, MD; SriniVas R. Sadda, MD; and Rishi P. Singh, MD

This course has expired. You can still review the content but course credit is no longer available.

Supplement Credits: 1

This continuing medical education (CME) activity captures content from a CME roundtable discussion held in October 2014 in Chicago, IL.

This certified CME activity is designed for retina specialists and general ophthalmologists involved in the management of patients with retinal disease

Expiration Date: Thursday, March 31, 2016
Release Date: March 2015

Learning Objectives

Upon completion of this activity participants should be able to:

  • Understand the present an anticipated public health burden attributed to diabetic eye disease and DME
  • Differentiate existing DME therapy options from recent primary and secondary treatment
  • Interpret clinical research data comparing laser therapy to new DME treatment protocols
  • Review the use of intravitreal steroids as single and combined approaches to DME
  • Define complications and strategies to minimize vision loss with intravitreal steroids
  • Educate patients about treatment regimens and risks associated with DME
  • Improve practice management issues encountered with retinal therapies

Statement of Need

The impact of vision loss due to the ocular manifestations of diabetes is a major public health burden facing our society, given the large size of the aging population at risk due to obesity and metabolic disease complications. Significant challenges lie ahead in addressing the needs of patients at risk for vision loss, as well as the impact to society that comes with an increasing population with impaired vision. Patients with macular degeneration, retinal vein occlusion (RVO), and diabetic macular edema (DME) present related physiologic problems for retinal specialists and ophthalmologists in the management of these conditions. Given the coincident systemic disease associated with diabetic retinopathy (DR), the present and predicted financial health care impact is substantial.

According to the 2012 Vision Problems in the US Report from the Prevent Blindness America Foundation, diabetic retinopathy impacts more than 7.6 million people aged 40 years and older.1 This contributes significantly to the more than $50 billion in direct economic costs due to vision disorders in people aged 40 years and older.

As new therapies enter the market, treatment options and dosing strategies can be affected by the cost of treatment, which continues to be a major factor in treatment planning.2 Clinicians need to consider multiple therapy options in order to properly gauge the right treatment plan for any given patient’s needs.

More broadly, the American Diabetes Association confirms that more than 150 million people across the world are affected by diabetes. By 2025, that number is projected to reach 324 million, including 35% who are expected to develop diabetic retinopathy.3 Monitoring, diagnosing, and treating the vision care needs of this potential population of over 100 million persons is daunting. For nearly 20 years, DR has been documented as the leading cause of blindness and decreased vision-related quality of life in working-age Americans.4,5,6 DME frequently follows the onset of nonproliferative diabetic retinopathy, resulting from abnormal capillary permeability and associated leakage of fluid leakage into the tissue of the retina. In recent years, new understanding of the pathophysiology of DME has focused researchers on the involvement of intracellular hyperglycemia, which induces free radicals (oxidative stress), protein kinase C activation, and formation of advanced glycation end-products.7 This process results in hypoxia, ischemia, inflammation, and alteration of vitreomacular interface. Inflammation produces an increase in VEGF production, endothelial dysfunction, leukocyte adhesion, and protein kinase C production. In fact, diabetic retinopathy is now considered to be a state of low-grade inflammation.8

When not treated properly, which is often the case, DME progresses to proliferative DR and retinal neovascularization, hemorrhaging, and permanent vision loss. Approximately 50% of untreated patients with proliferative DR will become blind within 5 years of the initial diagnosis.9 Such outcomes can frequently be avoided, however. Both decreased vision and decreased vision-related quality of life may be modified by treatment, including new modalities that provide practitioners with the flexibility of customizing management based on each patient’s individual needs.

Focal macular laser photocoagulation (FML) has been the primary treatment for DME for more than 2 decades. The Early Treatment Diabetic Retinopathy Study (ETDRS) outcomes focused on the preservation of vision, finding a 50% reduction in the likelihood of severe vision loss with grid-style FML.10 In 2010, the Diabetic Retinopathy Clinical Research Network (DRCR.net) reported a 10-letter gain in nearly one-third of patients treated with laser, but 19% of the subjects experienced progressive vision loss.11 Emerging therapies have recently shown promise, both as adjunctive and possibly first-line alternatives to laser therapy. Several pharmaceutical therapies for DME are currently in clinical development, the majority of which are intravitreally injected anti-inflammatory or anti-angiogenic agents. These include VEGF inhibitors, such as ranibizumab (Lucentis, Genentech), aflibercept (VEGF Trap-Eye, Regeneron) and pegaptanib sodium (Macugen, OSI Eyetech), as well as intravitreal delivery systems, which release corticosteroids, such as fluocinolone acetonide (Iluvien, Alimera), dexamethasone (Ozurdex, Allergan), and triamcinolone acetonide (I-vation SurModics).

A study conducted by the DRCR.net has shown that patients treated with 0.5 mg ranibizumab plus prompt (n = 187) or deferred (≥ 24 weeks) laser (n = 188) had better visual acuity outcomes at 1 year than patients who received sham injections plus prompt laser treatments (n = 293).12 Outcome measures in the study included change in visual acuity and mean central subfield thickness measurements. Visual acuity improvement (± standard deviation) was significantly better in the ranibizumab plus prompt laser group (+9 ± 12, P<0.001) and in the ranibizumab plus deferred laser group (+9, ± 12, P < 0.001), compared to those undergoing sham injections plus prompt laser (+3 ±13) treatments. Visual acuity was not significantly better compared to patients treated with triamcinolone plus prompt laser (+4 ± 13, P=0.3). Reduction in mean central subfield thickness was similar in all studied groups. Cataract progression and intraocular pressure increases were more frequent in the triamcinolone plus laser group.

More recently, researchers revealed the 2-year primary outcomes of RISE and RIDE, which also focused on the treatment of DME. These phase 2 and 3 studies evaluated 0.3-mg and 0.5-mg doses of ranibizumab compared to sham injections, evaluating subjects who were randomized to sham treatments and focal/grid laser photocoagulation. The RISE and RIDE studies clearly demonstrated that monthly injections of ranibizumab were associated with significant improvement in visual acuity: 40% to 45% of patients gained 3 or more ETDRS lines of vision.13 Besides the gain in visual acuity, patients who were treated with ranibizumab had fewer overall complications from their underlying DR and less progression of the DR than those who were treated with sham injections. Another finding of the RISE and RIDE studies was that no statistically significant differences in side effects or serious systemic or ocular adverse events were associated with subjects treated with ranibizumab injections or sham injections.

In READ 3, patients with DME were treated with multiple injections of either 0.5 mg or 2 mg of ranibizumab. The mean increase in visual acuity was 8.7 letters for the 0.5-mg group and 7.5 letters for the 2-mg group. Visual acuity and central retinal thickness changes were maintained up to the 1-year evaluation.14

In 2011, the RESTORE study demonstrated superior gains in best-corrected visual acuity at 1 year with ranibizumab with or without laser versus laser monotherapy.15 In contrast to READ-2, the authors found greater reduction in foveal thickness in the anti-VEGF groups, as well as better vision-related quality of life. The number of total injections over the year for the injection-only group was 7.1 versus 4.8 in the combination therapy group.

The FAME Study found that 2 doses of the fluocinolone implant significantly improved visual acuity in DME over 2 years.16 The insert can be administered in an outpatient procedure through a 25-gauge needle. However, the FDA indicated that it would require 2 additional clinical trials to resolve safety concerns raised by investigators.17 Although intravitreal corticosteroids have the added benefit of targeting the inflammatory component of DME, the clinical benefits have been less impressive. Intravitreal corticosteroids may be an appropriate option with or without FML treatment in nonresponders who are pseudophakic or those who have had successful filtration surgery to control intraocular pressure (DRCR.net protocol I, phase 3 FAME trial, phase 3 PLACID trial).18-20

The DA VINCI study, a phase 2 randomized clinical trial, showed that all doses and dosing regimens of aflibercept that were tested were superior to laser for centrally involved DME.21 A significant increase in BCVA from baseline was achieved at week 24 and maintained or improved at week 52 for all aflibercept dosing groups. When aflibercept was administered every 2 months or on an as-needed basis, these regimens were just as effective as monthly treatments.

A new 2013 report from the PLACID study demonstrated higher gains in BCVA up to 9 months posttreatment for diffuse DME in patients receiving dexamethasone intravitreal implant 0.7 mg combined with laser photocoagulation compared with laser alone, but no significant between-group differences at 12 months.22

Most recently, Alimera Sciences announced that the FDA has rejected “the sustained-released Iluvien (fluocinolone acetonide) intravitreal implant for the treatment of diabetic macular edema” due to safety concerns.23 It is presently unknown if additional clinical trials will be undertaken in the US in order to seek future approval for DME treatment.

Also of recent note in 2013, 2 phase 3 comparison studies (VIVID-DME and VISTA-DME) demonstrated positive 1-year results for treatment of DME comparing aflibercept to laser photocoagulation.24 Subjects were randomized into 3 arms: 2 mg of intravitreal aflibercept injected monthly, 2 mg of intravitreal aflibercept injected every other month (after 5 initial monthly injections), or laser photocoagulation. In both studies, the 2-mg aflibercept treatments demonstrated mean increases from baseline in visual acuity of 10.5 to 12.7 letters, while photocoagulation treatment demonstrated mean increases of 0.2 letters in VISTA-DME (P < 0.0001) and 1.2 letters in VIVID-DME (P < 0.0001). Ocular complications were reported as conjunctival hemorrhage, eye pain, and vitreous floaters. Three-year follow-up is planned.

Photocoagulation remains the gold standard for the treatment of DME. However, continuing increases in studies evaluating different therapies may lead to a better understanding of pathophysiology and lead to more efficacious treatments. Because of the continuation of research designed to investigate pathophysiology and the rapid evolution of multiple clinical trials with emerging treatments, updated information on new diagnostic and treatment trends has become increasingly important to retina specialists, as well as other ophthalmologists who treat patients with DME.

A full knowledge of the dynamics of retinal therapeutic treatment options will be beneficial for arming both specialists and general ophthalmologists who use these drugs with a more complete understanding when counseling patients and initiating treatment. It is expected that providing this education would remove a potential barrier to greater acceptance of this area of disease management. Addressing optimal practice management strategies can improve the efficiency and delivery of care to this growing pool of patients at risk for vision loss. Finally, in the interest of providing more complete care to patients, arming clinicians with current insight into the management strategies for retinal therapeutics may assist in the reduction of treatment complications and further vision loss.


1. Prevent Blindness America, 2012 Vision Problems in the U.S. Available at: www.preventblindness.org/sites/
default/files/national/documents/state-fact-sheets/VPUS%2BCOV_FS_US.pdf. Accessed March 6, 2015.
2. Managed Care Implications of Age-Related Ocular Conditions. Available at: www.ajmc.com/publications/
Accessed March 6, 2015.
3. Hogan P, Dall T, Nikolov P; American Diabetes Association. Economic costs of diabetes in the US in 2002.
Diabetes Care. 2003;26(3):917-932.
4. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases. Diabetes in
America, 2nd ed. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases:
Bethesda, MD, 1995.
5. Klein R, Knudtson MD, Lee KE, et al. The Wisconsin Epidemiologic Study of Diabetic Retinopathy: XVIII. The 14-year
incidence and progression of diabetic retinopathy and associated risk factors in type 1 diabetes. Ophthalmology.
6. Hariprasad SM, Mieler WF, Grassi M, et al. Vision-related quality of life in patients with diabetic macular oedema.
Br J Ophthalmol. 2008;92:89-92.
7. Bhagat N, Grigorian RA, Tutela A, Zarbin MA. Diabetic macular edema: pathogenesis and treatment. Surv
Ophthalmol. 2009;54(1):1-32.
8. Singh A, Stewart JM. Pathophysiology of diabetic macular edema. Int Ophthalmol Clin. 2009;49(2):1-11.
9. Hamilton AMP, Ulbig MW, Polkinghorne P. Management of Diabetic Retinopathy. BMJ Publishing Group:
London, 1996.
10. Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study report number 1.
Early Treatment Diabetic Retinopathy Study research group. Arch Ophthalmol. 1985;103:1796-1806.
11. Diabetic Retinopathy Clinical Research Network. Factors associated with improvement and worsening of visual
acuity 2 years after focal/grid photocoagulation for diabetic macular edema. Ophthalmology. 2010;117:946-953.
12. Elman MJ, Aiello, LP, Beck RW, et al; The Diabetic Retinopathy Clinical Research Network. Randomized trial
evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular
edema. Ophthalmology. 2010;117(6): 1064-1077.e35
13. Boyer DS. Ranibizumab for diabetic macular edema: 24-month results of RIDE and RISE, two phase 3 randomized
trials. Presented at 2011 Retina Subspecialty Day/American Academy of Ophthalmology Annual Meeting;
October 22, 2011; Orlando, FL.
14. Nguyen QD. READ 3: 0.5-mg vs 2.0-mg ranibizumab for diabetic macular edema. Presented at 2011 Retina
Subspecialty Day/American Academy of Ophthalmology Annual Meeting; October 22, 2011; Orlando, FL.
15. The RESTORE Study Group. The RESTORE study: Ranibizumab monotherapy or combined with laser versus laser
monotherapy for diabetic macular edema. Ophthalmology. 2011;118:615-625.
16. Campochiaro PA, Brown DM, Pearson A, et al; FAME Study Group. Long-term benefit of sustained-delivery
fluocinolone acetonide vitreous inserts for diabetic macular edema. Ophthalmology. 2011;118(4):626-635.e2.
17. Alimera Sciences receives complete response letter from FDA for ILUVIEN®. November 11, 2011. Available at:
18. Diabetic Retinopathy Clinical Research Network. Expanded 2-year follow-up of ranibizumab plus prompt or
deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology. 2011;118:609-614.
19. Pearson PA, Comstock TL, Ip M, et al. Fluocinolone acetonide intravitreal implant for diabetic macular edema: a
3-year multicenter, randomized, controlled clinical trial. Ophthalmology. 2011;118:1580-1587.
20. Safety and efficacy of a new treatment in combination with laser for diabetic macular edema. ClinicalTrials.gov
Web site. Available at: http://clinicaltrials.gov/ct2/show/NCT00464685. Accessed March 6, 2015.
21. Do DV, Nguyen QD, Boyer D, et al.; DA VINCI Study Group. One-year outcomes of the DA VINCI Study of VEGF
Trap-Eye in eyes with diabetic macular edema. Ophthalmology. 2012;119(8):1658-1665.
22. Callanan DG, Gupta S, Boyer DS, et al.; Ozurdex PLACID Study Group. Dexamethasone intravitreal implant in
combination with laser photocoagulation for the treatment of diffuse diabetic macular edema. Ophthalmology.
23. Alimera Sciences, Inc. press release, October 18, 2013. Available at: http://eyewiretoday.com/view.
24. Regeneron and Bayer report positive one-year results from two phase 3 trials of EYLEA® (aflibercept)
injection for the treatment of diabetic macular edema. Available at: http://investor.regeneron.com/releasedetail.
cfm?ReleaseID=782911. Updated August 6, 2013. Accessed March 6, 2015.

Faculty and Disclosures

Allen C. Ho, MD
Director of Retina Research at Wills Eye Hospital
Professor of Ophthalmology
Thomas Jefferson University
Philadelphia, PA
Chief Medical Editor, Retina Today

Michael D. Ober, MD
Retina Consultants of Michigan
Member, Adjunct Teaching Faculty
Department of Ophthalmology
Henry Ford Health Systems
Detroit, MI

SriniVas R. Sadda, MD
Professor of Ophthalmology
Doheny Eye Institute
University of Southern California
Los Angeles, CA
Rishi P. Singh, MD
Staff Physician
Cole Eye Institute, Cleveland Clinic
Medical Director of the Clinical Systems Office
Cleveland Clinic
Assistant Professor of Ophthalmology
Case Western University
Cleveland, OH



The views and opinions expressed in this educational activity are those of the faculty and do not necessarily represent the views of The Dulaney Foundation and Retina Today.

Policy on Privacy and Confidentiality

In accordance with the disclosure policies of The Dulaney Foundation and to conform with ACCME and US Food and Drug Administration guidelines, anyone in a position to affect the content of a CME activity is required to disclose to the activity participants (1) the existence of any financial interest or other relationships with the manufacturers of any commercial products/devices or providers of commercial services and (2) identification of a commercial product/device that is unlabeled for use or an investigational use of a product/device not yet approved.


Current Insight Into Retinal Disease Management: Focus on DME and Intravitreal Corticosteroids

Allen C. Ho, MD, Moderator; Michael D. Ober, MD; SriniVas R. Sadda, MD; and Rishi P. Singh, MD