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This continuing medical education (CME) activity captures content from a live CME symposium held in October 2014 in Chicago, Illinois.
Participants should read the CME activity in its entirety. After reviewing the material, please complete the self-assessment test, which consists of a series of multiple-choice questions. To answer these questions online and receive real-time results, please visit www.dulaneyfoundation.org and click “Online Courses.” Upon completing the activity and achieving a passing score of higher than 70% on the self-assessment test, you may print out a CME credit letter awarding 1 AMA PRA Category 1 Credit.™ The estimated time to complete this activity is 1 hour.
This certified CME activity is designed for retina specialists and general ophthalmologists involved in the management of patients with retinal disease.
The impact of vision loss due to the ocular manifestations of diabetes is a major public health burden facing our society, given the large 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 on society that comes with an increasing population with impaired vision. Macular degeneration, retinal vein occlusion (RVO), and diabetic macular edema (DME) cause 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, DR affects more than 7.6 million individuals aged 40 years and older.1 This contributes significantly to the more than $50 billion in direct economic costs to due vision disorders in this age group. As new therapies enter the market, treatment options and dosing strategies can have an impact on the cost of treatment, which continues to be a major factor in treatment planning.2 Clinicians need to consider multiple options in order to properly gauge the right treatment plan for any given patient’s needs.
More broadly, the American Diabetes Association confirms that over 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.4-6 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 (PKC) activation, and formation of advanced glycation end-products (AGE).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 PKC production. In fact, DR is now considered to be a state of low-grade inflammation.8 DR is the most common microvascular complication of diabetes and remains one of the leading causes of blindness worldwide among adults aged 20 to 74 years. The two most important visual complications of DR are DME and proliferative DR (PDR). The prevalence of DR increases with the duration of diabetes, and nearly all individals with type 1 diabetes and more than 60% of those with type 2, have some form of retinopathy after 20 years. According to a Wisconsin epidemiologic study of DR (WESDR),9 3.6% of younger-onset patients (type 1 diabetes) and 1.6% of older-onset patients (type 2 diabetes) were legally blind.
A study conducted by the DRCR.net10 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). 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 < .001) and in the ranibizumab plus deferred laser group (+9, ± 12, P < .001), compared to those undergoing sham injections plus prompt laser (+3 ±13) treatments. Visual acuity was not significantly better compared with patients treated with triamcinolone plus prompt laser (+4 ± 13, P = .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,11 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. Besides the gain in visual acuity, patients who were treated with ranibizumab overall had fewer complications from their underlying DR and less progression of the DR than those who were treated with sham injections. In addition, 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 the READ-3 trial,12 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.
In 2011, the RESTORE study13 demonstrated superior gains in best-corrected visual acuity at 1 year with ranibizumab with or without laser versus laser monotherapy. 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 Study14 found that two doses of the fluocinolone implant significantly improved visual acuity in DME over 2 years. The insert can be administered in an outpatient procedure through a 25-gauge needle. However, the FDA indicated that it would require two additional clinical trials to resolve safety concerns raised by investigators.15
The DA VINCI study,16 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. A significant increase in BCVA from baseline was achieved at week 24 and was 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 PLACID17 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.
Also of recent note in 2013, two phase 3 comparison studies (VIVID-DME and VISTA-DME18) demonstrated positive 1-year results for treatment of DME comparing aflibercept to laser photocoagulation. Subjects were randomized into three arms: 2 mg of intravitreal aflibercept injected monthly, 2 mg of intravitreal aflibercept injected every other month (after five 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 VISTADME (P < .0001) and 1.2 letters in VIVID-DME (P < .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 have become increasingly important to retina specialists, as well as other ophthalmologists who treat patients with DME.
1. Prevent Blindness America, 2012 Vision Problems in the US. Available at: www.preventblindness.org/sites/default/files/national/documents/state-fact-sheets/VPUS%2BCOV_FS_US.pdf. Accessed March 25, 2015.
2. Managed Care Implications of Age-Related Ocular Conditions. Available at: www.ajmc.com/publications/supplement/2013/ACE011_13may_AgingEye/ACE011_13May_AgingEye_Cardarelli/#sthash.9vzoQ1SX.dpuf. Accessed March 25, 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. 1998;105:1801-1815.
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. Fong DS, Aiello L, Gardner TW, King GL, Blankenship G, Cavallerano JD, et al. American Diabetes Association. Diabetic retinopathy. Diabetes Care. 2003;26:226–9.
10. 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
11. Brown DM, Nguyen QD, Marcus DM, et al; RIDE and RISE Research Group. 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
12. 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.
13. 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.
14. 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.
15. Alimera Sciences receives complete response letter from FDA for ILUVIEN®. November 11, 2011. Available at: http://investor.alimerasciences.com/releases.cfm?Year=&ReleasesType=&PageNum=5. Accessed March 25, 2015.
16. 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.
17. 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. 2013;120(9):1843-1851.
18. 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. Accessed March 25, 2015.
The views and opinions expressed in this educational activity are those of the faculty and do not necessarily represent the views of Allergan, The Dulaney Foundation, or Retina Today.
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.