Emily D. Cole, BS; Eduardo A. Novais, MD; and Nadia K. Waheed, MD, MPH

Diabetic retinopathy affects more than 90 million people worldwide and is the most frequent cause of legal blindness among working-age individuals in developed countries.^1–3 Although diabetes mellitus may cause vision loss by several means including optic neuropathy, cataract formation, macular ischemia, and proliferative retinopathy, diabetic macular edema (DME) is the most common reason for moderate visual loss in diabetes.^2,4

The pathogenesis of DME is multifactorial and may include contributing factors such as mechanical traction, upregulation and downregulation of a variety of cytokines including vascular endothelial growth factor (VEGF), and inflammation.⁵ Hyperglycemia leads to high intracellular levels of glucose, formation of free radicals, and protein kinase C activation,⁶ which in turn leads to disruption of the blood-retinal barrier and increased accumulation of fluid into the retina.^7–10 Other influential factors include hypoxia, altered blood flow, and retinal ischemia.

The Early Treatment Diabetic Retinopathy Study (ETDRS) group established level-one guidelines for the use of macular laser photocoagulation to treat patients with clinically significant DME.¹¹ In the ETDRS, focal photocoagulation reduced the risk of moderate visual acuity loss (defined as a loss of 15 or more letters) by approximately 50%, from 24% to 12%, after 3 years.¹² However, these clinical laser treatment guidelines were established before the use of adjunctive pharmacologic agents.

In the past decade, novel pharmacologic therapies have shifted treatment paradigms away from laser photocoagulation. Of these, intravitreal anti-VEGF agents are the most widely used and have shown substantial improvements both in visual and anatomic outcomes (Figure 9-1).^13–19 However, one of the main drawbacks of anti-VEGF therapy is its short duration of action, requiring many patients to undergo repeated intravitreal injections.²⁰

Inflammatory factors have been associated with macular edema of different etiologies. Intraocular corticosteroids have been used as adjunctive or alternative treatments for DME, and work by inhibiting inflammatory cytokines and decreasing vascular permeability.5,21 Intravitreal triamcinolone was evaluated previously as a treatment for DME in a randomized trial conducted by the Diabetic Retinopathy Clinical Research Network (DRCR.net).²² Although the data suggested that intravitreal triamcinolone was superior to observation in the ETDRS, it was not superior to focal/grid photocoagulation.²³ The United States Food and Drug Administration (FDA) later approved a dexamethasone intravitreal implant (Ozurdex) for treating DME, in addition to macular edema associated with noninfectious posterior uveitis and retinal vein occlusion. This sustained-release formulation was designed to release dexamethasone for up to 6 months, eliminating the need for monthly injections.²⁴ Functional and anatomic improvements with Ozurdex have been reported in several case series of patients with persistent DME.^25–27 However, steroid-related adverse events such as cataract formation and increased intraocular pressure, as well as migration of implants into the anterior chamber requiring surgical removal, can complicate treatment.²⁸

VEGF blockade can be achieved by targeting extracellular anti-VEGF, inhibiting VEGF receptor expression, or via antibodies that bind to the VEGF molecule to prevent receptor binding. There are multiple agents used in the management of DME. Currently, ranibizumab, bevacizumab, and aflibercept are the most commonly used.29–34 Ocular imaging, including color fundus photography, optical coherence tomography (OCT), and more recently OCT angiography, has been useful in the management of DME (Figures 9-2 and 9-3) and deciding when to treat with these anti-VEGF agents.

Pegaptanib, the first anti-VEGF agent approved for the treatment of neovascular age-related macular degeneration (AMD), is a 28-nucleotide aptamer that binds to and inactivates the extracellular VEGF₁₆₅ isomer. It has an intermediate level of diffusion ability and heparin binding ability, which corresponds to the ability to bind to cell surfaces and basement membranes.30 It has been associated with improved visual outcomes and a reduction in mean central subfoveal thickness (CST) in patients with DME, with a comparable safety profile when compared to sham.³⁵

In 2005, a phase II randomized trial compared multiple concentrations of pegaptanib to sham treatment for DME. The 0.3 mg group had significantly greater gains in visual acuity (VA), a reduction in the mean CST, and fewer patients requiring laser compared to sham.³⁵ The subsequent phase II/III trial also demonstrated benefit of pegaptanib over sham, with 36.8% of patients receiving pegaptanib gaining more than 10 letters compared to 19.7% in the sham group at week 54. At all points within the 2-year follow-up, the change in mean VA from baseline was significantly greater in patients treated with pegaptanib than sham. This study also looked at longer-term safety of the drug and found that the sham and treated groups had similar numbers of adverse events and frequency of discontinuation.36 Today, pegaptanib is rarely used in clinical practice because the comparative efficacy of the drug is lower than other available treatment options.

Ranibizumab

Ranibizumab is a humanized monoclonal antibody fragment derived from bevacizumab, a full-length humanized antibody. It binds all isoforms of VEGF-A and active proteolytic fragments and was designed for better penetration into the retina because of its smaller size. It was first approved for the treatment of neovascular AMD and has also been extensively studied in clinical trials for the treatment of DME.^37–39

The READ-2 study provided early evidence that ranibizumab was effective in the treatment of DME, and that combining focal and grid laser with ranibizumab may decrease the frequency of injections needed to control edema for at least 2 years. The READ-3 studies compared 2 different doses of ranibizumab (0.5 mg and 2 mg), and demonstrated that a higher dose did not show significant benefits over a 6-month period.^19,40,41 The RIDE and RISE studies were 2 identical phase III multicenter studies that led to the approval of 0.3 mg ranibizumab by the FDA for DME. Both studies showed that a significantly higher number of patients with center-involved DME treated with 0.3 mg ranibizumab gained 15 or more letters at month 24 compared to those treated with sham. These results were equivalent to those seen with 0.5 mg ranibizumab, thus leading to the approval of the lower dose. Treated patients also required fewer macular laser procedures. Improvements in macular edema on OCT as well as the degree of retinopathy were also found to improve. In the extension phase of both studies, patients could cross over from the sham group into the monthly treatment arm, creating a delayed treatment initiation group. These patients gained VA but not to the degree of those treated with early initiation of ranibizumab therapy.^42,43 This demonstrated that intraocular anti-VEGF treatment should be initiated early to maximize visual acuity outcomes.

The DRCR.net performed a randomized clinical trial comparing ranibizumab with prompt or deferred laser and found that ranibizumab combined with both prompt or deferred laser had greater VA gains than laser alone. Similar gains in VA were also seen in pseudophakic eyes treated with triamcinolone. In the expanded 2-year follow-up, compared to sham, the mean change in the VA letter score from baseline was 3.7 letters greater in the ranibizumab plus prompt laser group, 5.8 letters greater in the ranibizumab plus deferred laser group, and 1.5 letters less in the triamcinolone plus prompt laser group. This difference in the steroid-treated group was found to be due to the development of cataract, which was more frequent in the triamcinolone plus prompt laser group. Forty percent of the eyes in both ranibizumab groups still had central macular edema after 2 years.^44,45

The RESTORE and REVEAL studies were phase III trials that demonstrated ranibizumab was superior to laser therapy alone. In the 3-year extension of the RESTORE study, ranibizumab improved VA and decreased CST on OCT on a pro re nata (PRN), or as-needed, treatment regimen.^17,46,47 The REVEAL study compared ranibizumab to laser in an Asian population, and found that ranibizumab monotherapy or ranibizumab combined with laser had superior VA improvements over laser treatment alone.48 Furthermore, there was not an increased rate of ocular or nonocular severe adverse events compared to sham in the RESOLVE trial.¹⁸

Recently, Protocol T from the DRCR.net compared the effectiveness of ranibizumab, aflibercept, and bevacizumab for center-involved DME over 2 years. All 3 groups showed improvement in VA, decreased frequency of visits, and decreased requirement of laser photocoagulation after 2 years. In the first year, aflibercept was found to be associated with greater gains in VA compared to the other 2 agents when baseline vision was 20/50 or worse. In eyes with baseline vision better than 20/50, there was no difference in visual acuity gains over 1 or 2 years although patients treated with bevacizumab were less likely to have OCT findings of less than 250 μm CST.^49,50

Bevacizumab

Bevacizumab is one of the most widely used anti-VEGF agents because of its low cost compared to the other agents. It is a full-length humanized antibody that is active against all isoforms of VEGF-A and competitively inhibits them in the extracellular space. It is FDA approved for the treatment of metastatic colon cancer but is used off-label for the treatment of AMD, DME, and several other ocular diseases. Michels et al⁵¹ initially proposed the use of bevacizumab as an intravitreal treatment for neovascular AMD in 2005, when they noticed VA improvement in patients treated with systemic bevacizumab for metastatic colorectal cancer.⁵¹

Protocol H of the DRCR.net was a short-term pilot study designed to evaluate the short-term effects of bevacizumab (1.25 mg and 2.5 mg) compared to focal laser. There was a significant reduction in CST in both treatment groups over 3 weeks but no significant difference in functional or anatomic outcomes between the groups. However, the initial positive response to patients treated with bevacizumab was also seen in the focal laser group after 3 weeks. Data from this study provided limited early evidence that bevacizumab may be beneficial in some eyes with DME.⁵²

Subsequent work by Ahmadiah, Faghihi, and Soheilian built on the DRCR.net findings and explored the combination of bevacizumab and triamcinolone. None of the studies found strong evidence that the addition of triamcinolone led to improved functional or visual outcomes. In a 2-year follow-up study comparing bevacizumab, bevacizumab plus triamcinolone, and macular photocoagulation, no significant differences in visual outcomes among the 3 groups were noted.^53–57

The Bevacizumab or Laser Therapy (BOLT) trial was a randomized, controlled trial over 2 years that compared intravitreal bevacizumab to macular laser therapy in patients with a history of macular laser. After one year, patients treated with bevacizumab had significantly better VA, gained a mean of 8.6 letters compared to a loss of 0.5 letters in the laser-treated arm, and had no serious adverse events noted after 12 months. This prospective study supported the long-term use of bevacizumab for DME.⁵⁸

Protocol T also found similar rates of serious adverse events, hospitalizations, and ocular adverse events between the anti-VEGF agents. Although a post hoc analysis showed a higher frequency of cardiac and vascular disorders in the ranibizumab group, this was thought to be secondary to other confounding factors and not to be of clinical significance.⁵⁹ Moreover, several other studies have failed to reproduce this difference in adverse events between the various different anti-VEGF agents.

Aflibercept is a recombinant fusion protein that acts as a decoy receptor and binds VEGF-A, VEGF-B, and placental growth factor. It binds with much higher affinity than ranibizumab and bevacizumab. Also originally used as a chemotherapy agent, it has since been FDA approved for ocular use in DME, neovascular AMD, and macular edema due to retinal vein occlusion.16,60–62

The DA VINCI study was a phase II trial that demonstrated aflibercept to be superior to macular laser treatment for DME over a 24-week period. The study compared multiple dosages and dosing regimens and found that in all dosing groups, VA was significantly improved and there were greater reductions in retinal thickness compared with laser treatment. The study was not powered to detect differences between the dosage groups, but all showed superiority to laser.^63,64

The VIVID and VISTA studies were 2 identical phase III trials that led to the approval of aflibercept by the FDA for the treatment of DME. In these studies, eyes were randomized to receive 2 mg aflibercept every 4 weeks, 2 mg aflibercept every 8 weeks after 5 initial monthly doses, or macular laser. The 1-year and 100-week follow-up demonstrated that aflibercept was more effective compared to laser. At month 12, the mean change in VA (+12.5 vs +0.2 letters) and CST values (−185.9 vs −73.3 μm) were significantly greater with aflibercept compared to laser therapy. The mean change in VA improvement was noted through the 100-week follow-up (+11.3 vs +0.8 letters), suggesting the drug was still effective with long-term administration. The only adverse event noted in these studies over the long-term follow-up was the development of cataract.⁶⁵

The results from Protocol T suggested the importance of baseline visual acuity when comparing the 3 agents. In the first year, aflibercept was found to be associated with greater gains in VA compared to the other 2 agents when baseline vision was 20/50 or worse. In eyes with baseline vision better than 20/50, there was no difference in VA gains over 2 years. Patients treated with aflibercept, however, were less likely to require subsequent laser photocoagulation.^49,50,66 Results from Protocol T have sparked debate regarding which agent should be used to initiate treatment in patients with VA less than 20/50 and the role of bevacizumab and ranibizumab nonresponders in driving the results. One option is to initiate treatment with bevacizumab and subsequently switch to aflibercept if there is no treatment response. Another option is to initiate treatment with aflibercept then continue with a hybrid of multiple agents for more long-term treatment. Currently, there is no clear evidence-based recommendation on the best anti-VEGF to use.

Conclusion

The development of anti-VEGF agents has revolutionized the treatment of vision-threatening chorioretinal diseases such as DME and neovascular AMD. Prior to this, laser photocoagulation was the main treatment option and visual outcomes were not as promising. Today, anti-VEGF agents are often the first-line treatment of choice for clinicians with a better visual prognosis with treatment. Current treatment paradigms vary; some treat on a monthly basis until stable, then continue on an as-needed basis, while others use a treat-and-extend approach. OCT is used extensively to quantify the macular edema and assess the success or failure of anti-VEGF therapy in these eyes. Although most studies investigated monthly treatment regimens for DME, this can be costly and often imposes an unrealistic burden on the patient, their families, and society. However, the DRCR.net PRN protocols provide good evidence that aggressive treatment, especially at the initiation, can lead to a good prognosis and reduced need for treatment after 1 to 2 years of aggressive “initiation” treatment. Moreover, there is emerging evidence that treatment for DME with anti-VEGF therapy may be disease modifying, with a regression of diabetic retinopathy in patients treated with anti-VEGF agents.67 This has led to a label change with the approval of ranibizumab and aflibercept for the treatment of diabetic retinopathy in the setting of DME. Anti-VEGF agents are now being studied in combination with other agents to try to increase the treatment interval and duration of action of these medications. Newer delivery systems are also being studied that would allow for slow release of the agent, requiring fewer invasive procedures and reducing side effects associated with intravitreal injections.

References

1.   Yau JW, Rogers SL, Kawasaki R, et al. Global prevalence and major risk factors of diabetic retinopathy. Diabetes Care. 2012;35(3):556-564.

2.   Moss SE, Klein R, Klein BE. The 14-year incidence of visual loss in a diabetic population. Ophthalmology. 1998;105(6):998-1003.

3.   Klein R, Klein BE, Moss SE, Cruickshanks KJ. The Wisconsin Epidemiologic Study of Diabetic Retinopathy: XVII. The 14-year incidence and progression of diabetic retinopathy and associated risk factors in type 1 diabetes. Ophthalmology. 1998;105(10):1801-1815.

4.   Klein R, Klein BE, Moss SE, Cruickshanks KJ. The Wisconsin Epidemiologic Study of Diabetic Retinopathy: XIV. Ten-year incidence and progression of diabetic retinopathy. Arch Ophthalmol. 1994;112(9):1217-1228.

5.   Antcliff RJ, Marshall J. The pathogenesis of edema in diabetic maculopathy. Semin Ophthalmol. 1999;14(4):223-232.

6.   Wolfensberger TJ, Gregor ZJ. Macular edema—rationale for therapy. Dev Ophthalmol. 2010;47:49-58.

7.   Witmer AN, Vrensen GF, Van Noorden CJ, Schlingemann RO. Vascular endothelial growth factors and angiogenesis in eye disease. Prog Retin Eye Res. 2003;22(1):1-29.

8.   Miyamoto K, Khosrof S, Bursell SE, et al. Prevention of leukostasis and vascular leakage in streptozotocin-induced diabetic retinopathy via intercellular adhesion molecule-1 inhibition. Proc Natl Acad Sci U S A. 1999;96(19):10836-10841.

9.   Kim W, Hudson BI, Moser B, et al. Receptor for advanced glycation end products and its ligands: a journey from the complications of diabetes to its pathogenesis. Ann N Y Acad Sci. 2005;1043:553-561.

10. Ramasamy R, Vannucci SJ, Yan SS, Herold K, Yan SF, Schmidt AM. Advanced glycation end products and RAGE: a common thread in aging, diabetes, neurodegeneration, and inflammation. Glycobiology. 2005;15(7):16R-28R.

11. 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.

12. Diabetic Retinopathy Clinical Research Network, Scott IU, Edwards AR, et al. A phase II randomized clinical trial of intravitreal bevacizumab for diabetic macular edema. Ophthalmology. 2007;114(10):1860-1867.

13. Boyer DS, Hopkins JJ, Sorof J, Ehrlich JS. Anti-vascular endothelial growth factor therapy for diabetic macular edema. Ther Adv Endocrinol Metab. 2013;4(6):151-169.

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):789-801.

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: report 2. Ophthalmology. 2010;117(6):1078-1086.e2.

16. Korobelnik JF, Do DV, Schmidt-Erfurth U, et al. Intravitreal aflibercept for diabetic macular edema. Ophthalmology. 2014;121(11):2247-2254.

17. Mitchell P, Bandello F, Schmidt-Erfurth U, et al. The RESTORE study: ranibizumab monotherapy or combined with laser versus laser monotherapy for diabetic macular edema. Ophthalmology. 2011;118(4):615-625.

18. Massin P, Bandello F, Garweg JG, et al. Safety and efficacy of ranibizumab in diabetic macular edema (RESOLVE Study): a 12-month, randomized, controlled, double-masked, multicenter phase II study. Diabetes Care. 2010;33(11):2399-2405.

19. Nguyen QD, Shah SM, Khwaja AA, et al. Two-year outcomes of the ranibizumab for edema of the mAcula in diabetes (READ-2) study. Ophthalmology. 2010;117(11):2146-2151.

20. Haller JA. Current anti-vascular endothelial growth factor dosing regimens: benefits and burden. Ophthalmology. 2013;120(5 Suppl):S3-S7.

21. Sarao V, Veritti D, Boscia F, Lanzetta P. Intravitreal steroids for the treatment of retinal diseases. ScientificWorldJournal. 2014;2014:989501.

22. Diabetic Retinopathy Clinical Research Network. A randomized trial comparing intravitreal triamcinolone acetonide and focal/grid photocoagulation for diabetic macular edema. Ophthalmology. 2008;115(9):1447-1449, 1449.e1-1449.e10.

23. Diabetic Retinopathy Clinical Research Network, Beck RW, Edwards AR, et al. Three-year follow-up of a randomized trial comparing focal/grid photocoagulation and intravitreal triamcinolone for diabetic macular edema. Arch Ophthalmol. 2009;127(3):245-251.

24. Chang-Lin JE, Attar M, Acheampong AA, et al. Pharmacokinetics and pharmacodynamics of a sustained-release dexamethasone intravitreal implant. Invest Ophthalmol Vis Sci. 2011;52(1):80-86.

25. Zalewski D, Raczynska D, Raczynska K. Five-month observation of persistent diabetic macular edema after intravitreal injection of Ozurdex implant. Mediators Inflamm. 2014;2014:364143.

26. Zucchiatti I, Lattanzio R, Querques G, et al. Intravitreal dexamethasone implant in patients with persistent diabetic macular edema. Ophthalmologica. 2012;228(2):117-122.

27. Medeiros MD, Alkabes M, Navarro R, Garcia-Arumí J, Mateo C, Corcóstegui B. Dexamethasone intravitreal implant in vitrectomized versus nonvitrectomized eyes for treatment of patients with persistent diabetic macular edema. J Ocul Pharmacol Ther. 2014;30(9):709-716.

28. Khurana RN, Appa SN, McCannel CA, et al. Dexamethasone implant anterior chamber migration: risk factors, complications, and management strategies. Ophthalmology. 2014;121(1):67-71.

29. Ho AC, Scott IU, Kim SJ, et al. Anti-vascular endothelial growth factor pharmacotherapy for diabetic macular edema: a report by the American Academy of Ophthalmology. Ophthalmology. 2012;119(10):2179-2188.

30. Salam A, DaCosta J, Sivaprasad S. Anti-vascular endothelial growth factor agents for diabetic maculopathy. Br J Ophthalmol. 2010;94(7):821-826.

31. Virgili G, Parravano M, Menchini F, Evans JR. Anti-vascular endothelial growth factor for diabetic macular oedema. Cochrane Database Syst Rev. 2014;10:CD007419.

32. Goyal S, Lavalley M, Subramanian ML. Meta-analysis and review on the effect of bevacizumab in diabetic macular edema. Graefes Arch Clin Exp Ophthalmol. 2011;249(1):15-27.

33. Nicholson BP, Schachat AP. A review of clinical trials of anti-VEGF agents for diabetic retinopathy. Graefes Arch Clin Exp Ophthalmol. 2010;248(7):915-930.

34. Demirel S, Argo C, Agarwal A, et al. Updates on the clinical trials in diabetic macular edema. Middle East Afr J Ophthalmol. 2016;23(1):3-12.

35. Cunningham ET Jr, Adamis AP, Altaweel M, et al. A phase II randomized double-masked trial of pegaptanib, an anti-vascular endothelial growth factor aptamer, for diabetic macular edema. Ophthalmology. 2005;112(10):1747-1757.

36. Sultan MB, Zhou D, Loftus J, Dombi T, Ice KS, Macugen 1013 Study Group. A phase 2/3, multi-center, randomized, double-masked, 2-year trial of pegaptanib sodium for the treatment of diabetic macular edema. Ophthalmology. 2011;118(6):1107-1118.

37. Bandello F, Berchicci L, La Spina C, Battaglia Parodi M, Iacono P. Evidence for anti-VEGF treatment of diabetic macular edema. Ophthalmic Res. 2012;48(Suppl 1):16-20.

39. Chun DW, Heier JS, Topping TM, Duker JS, Bankert JM. A pilot study of multiple intravitreal injections of ranibizumab in patients with center-involving clinically significant diabetic macular edema. Ophthalmology. 2006;113(10):1706-1712.

40. Do DV, Sepah YJ, Boyer D, et al. Month-6 primary outcomes of the READ-3 study (Ranibizumab for Edema of the mAcula in Diabetes-Protocol 3 with high dose). Eye (Lond). 2015;29(12):1538-1544.

41. Nguyen QD, Shah SM, Heier JS, et al. Primary end point (six months) results of the Ranibizumab for Edema of the mAcula in diabetes (READ-2) study. Ophthalmology. 2009;116(11):2175-2181.e1.

42. 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.

43. Do DV, Nguyen QD, Khwaja AA, et al. Ranibizumab for edema of the macula in diabetes study: 3-year outcomes and the need for prolonged frequent treatment. JAMA Ophthalmol. 2013;131(2):139-145.

44. Elman MJ, Bressler NM, Qin H, et al. Expanded 2-year follow-up of ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology. 2011;118(4):609-614.

45. Diabetic Retinopathy Clinical Research Network, Elman MJ, Aiello LP, 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.e35.

46. Schmidt-Erfurth U, Lang GE, Holz FG, et al. Three-year outcomes of individualized ranibizumab treatment in patients with diabetic macular edema: the RESTORE extension study. Ophthalmology. 2014;121(5):1045-1053.

47. Mitchell P, Massin P, Bressler S, et al. Three-year patient-reported visual function outcomes in diabetic macular edema managed with ranibizumab: the RESTORE extension study. Curr Med Res Opin. 2015;31(11):1967-1975.

48. Ishibashi T, Li X, Koh A, et al. The REVEAL Study: ranibizumab monotherapy or combined with laser versus laser monotherapy in Asian patients with diabetic macular edema. Ophthalmology. 2015;122(7):1402-1415.

49. Diabetic Retinopathy Clinical Research Network, Wells JA, Glassman AR, et al. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. N Engl J Med. 2015;372(13):1193-1203.

50. Wells JA, Glassman AR, Ayala AR, et al. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema: two-year results from a comparative effectiveness randomized clinical trial. Ophthalmology. 2016;123(6):1351-1359.

51. Michels S, Rosenfeld PJ, Puliafito CA, Marcus EN, Venkatraman AS. Systemic bevacizumab (Avastin) therapy for neovascular age-related macular degeneration twelve-week results of an uncontrolled open-label clinical study. Ophthalmology. 2005;112(6):1035-1047.

52. Diabetic Retinopathy Clinical Research Network, Elman MJ, Qin H, et al. Intravitreal ranibizumab for diabetic macular edema with prompt versus deferred laser treatment: three-year randomized trial results. Ophthalmology. 2012;119(11):2312-2318.

53. Soheilian M, Ramezani A, Bijanzadeh B, et al. Intravitreal bevacizumab (Avastin) injection alone or combined with triamcinolone versus macular photocoagulation as primary treatment of diabetic macular edema. Retina. 2007;27(9):1187-1195.

54. Faghihi H, Roohipoor R, Mohammadi SF, et al. Intravitreal bevacizumab versus combined bevacizumab-triamcinolone versus macular laser photocoagulation in diabetic macular edema. Eur J Ophthalmol. 2008;18(6):941-948.

55. Ahmadieh H, Taei R, Riazi-Esfahani M, et al. Intravitreal bevacizumab versus combined intravitreal bevacizumab and triamcinolone for neovascular age-related macular degeneration: six-month results of a randomized clinical trial. Retina. 2011;31(9):1819-1826.

56. Ahmadieh H, Ramezani A, Shoeibi N, et al. Intravitreal bevacizumab with or without triamcinolone for refractory diabetic macular edema; a placebo-controlled, randomized clinical trial. Graefes Arch Clin Exp Ophthalmol. 2008;246(4):483-489.

57. Soheilian M, Ramezani A, Obudi A, et al. Randomized trial of intravitreal bevacizumab alone or combined with triamcinolone versus macular photocoagulation in diabetic macular edema. Ophthalmology. 2009;116(6):1142-1150.

58. Rajendram R, Fraser-Bell S, Kaines A, et al. A 2-year prospective randomized controlled trial of intravitreal bevacizumab or laser therapy (BOLT) in the management of diabetic macular edema: 24-month data: report 3. Arch Ophthalmol. 2012;130(8):972-979.

59. Comparison of Age-related Macular Degeneration Treatments Trials (CATT) Research Group, Martin DF, Maguire MG, et al. Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: two-year results. Ophthalmology. 2012;119(7):1388-1398.

60. Ciombor KK, Berlin J. Aflibercept—a decoy VEGF receptor. Curr Oncol Rep. 2014;16(2):368.

61. Papadopoulos N, Martin J, Ruan Q, et al. Binding and neutralization of vascular endothelial growth factor (VEGF) and related ligands by VEGF Trap, ranibizumab and bevacizumab. Angiogenesis. 2012;15(2):171-185.

62. Heier JS, Brown DM, Chong V, et al. Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration. Ophthalmology. 2012;119(12):2537-2548.

63. Do DV, Schmidt-Erfurth U, Gonzalez VH, et al. The DA VINCI Study: phase 2 primary results of VEGF Trap-Eye in patients with diabetic macular edema. Ophthalmology. 2011;118(9):1819-1826.

64. 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.

65. Brown DM, Schmidt-Erfurth U, Do DV, et al. Intravitreal aflibercept for diabetic macular edema: 100-week results from the VISTA and VIVID studies. Ophthalmology. 2015;122(10):2044-2052.

66. Heier JS, Bressler NM, Avery RL, et al. Comparison of aflibercept, bevacizumab, and ranibizumab for treatment of diabetic macular edema: extrapolation of data to clinical practice. JAMA Ophthalmol. 2016;134(1):95-99.

67. Osaadon P, Fagan XJ, Lifshitz T, Levy J. A review of anti-VEGF agents for proliferative diabetic retinopathy. Eye (Lond). 2014;28(5):510-520.

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