Managing DME in the Age of Second-Generation Therapies

With the advent of anti-VEGF medications and the use of intravitreal corticosteroids, retina specialists have many tools at their disposal in treating patients with diabetic macular edema (DME). The first studies on intravitreal triamcinolone showed short-term efficacy in reducing DME in cases refractory to laser therapy^1,2; however, longer-term follow-up showed waning efficacy compared with laser.^3,4 The MEAD study demonstrated that the intravitreal dexamethasone implant (Ozurdex, Abbvie) is an acceptable treatment for DME, and in head-to-head comparison, dexamethasone was noninferior to anti-VEGF therapy for treatment-naïve DME and may perform better in DME cases that are resistant to anti-VEGF agents.^3,5

The first generation of anti-VEGF drugs—bevacizumab (Avastin, Genentech/Roche), 2 mg aflibercept (Eylea, Regeneron), and ranibizumab (Lucentis, Genentech/Roche)—has provided excellent therapeutic options for clinicians in managing DME.^6-8 Recently, the landscape of therapy has undergone further changes with the FDA approval of faricimab (Vabysmo, Genentech/Roche) and 8 mg aflibercept (Eylea HD, Regeneron), both of which tout an increased time interval between injections with noninferior outcomes.^9,10

These second-generation therapies raise questions regarding the most appropriate management approach for patients with DME. There are many factors that clinicians must consider, including efficacy, safety, and duration of effect, that influence decision making for each patient.

EXTENDING TREATMENT

In the drug design of novel anti-VEGF medications, two important factors are efficacy and duration of treatment. The clinical trials for 8 mg aflibercept and faricimab focused on extending the treatment interval without sacrificing visual outcomes. The PHOTON and YOSEMITE/RHINE clinical trials for 8 mg aflibercept and faricimab, respectively, showed extended therapeutic duration and improvement in some anatomical markers compared with 2 mg aflibercept.^10,11

The central subfoveal thickness was significantly reduced, and a higher percentage of patients achieved absence of DME and resolution of intraretinal fluid with 8 mg aflibercept and faricimab compared with 2 mg aflibercept, showing some anatomic benefit to second-generation therapy.^9,11 The clinical implications of these trials are especially important because fewer clinic visits allow clinicians to care for more patients, and patients are less burdened by frequent follow-up appointments. In the PHOTON study, there was no significant difference in BCVA when 8 mg aflibercept was used at 8, 12, or 16 weeks¹¹; in TENAYA and LUCERNE, 59% to 66.9% of patients achieved every 16-week doing for DME.⁹ More research is needed to determine the true real-world efficacy to better educate our patients on expectations.

PROPER PATIENT SELECTION

In some clinical settings, these medications are used as step therapy when patients have an inadequate response to other agents, such as bevacizumab, ranibizumab, and 2 mg aflibercept. However, in some post-marketing trials, evidence suggests switch therapy improves central subfoveal thickness and visual acuity and increases the treatment interval for patients previously treated with other agents.^12,13 This is a compelling therapeutic option for patients with inadequate response to first-generation agents who may have required laser or corticosteroid implant therapy in the past.

Clinicians should take into consideration the dosing interval for each new therapy before recommending it to certain patients. For example, the package insert for 8 mg aflibercept calls for a loading dose of three injections, once every 28 days, followed by every 8 weeks +/- 1 week. This may pose a problem for patients with aggressive disease who may require more frequent dosing. A potential workaround may be supplementing with other anti-VEGF agents between the 8 mg aflibercept doses, although this strategy is not well-described in the literature. Faricimab does not have these same prescribing restrictions and allows for injections every 28 days for subsequent injections. In recalcitrant cases, faricimab may be a good option, given the more lenient dosing schedule compared with 8 mg aflibercept.

Intravitreal steroid therapy is an effective treatment option for DME, performing well versus anti-VEGF treatment.^3,5 However, there are the considerations of cataract formation in phakic patients and IOP concerns, making corticosteroids a second- or third-line agent for DME.

LOOKING AHEAD

Novel therapies for the treatment of DME have the potential to improve functional and anatomical outcomes while providing longer treatment intervals. DME treatment decisions are becoming more complex with a wider choice of drug and treatment regimens for our patients. Further real-world data will shed more light on the optimal personalized treatment strategies for patients with DME. Regardless, we strive to continue to improve functional and anatomical outcomes.

1. Jonas JB, Söfker A. Intraocular injection of crystalline cortisone as adjunctive treatment of diabetic macular edema. Am J Ophthalmol. 2001;132(3):425-427.

2. Martidis A, Duker JS, Greenberg PB, Rogers AH, Puliafito CA, Reichel E, Baumal C. Intravitreal triamcinolone for refractory diabetic macular edema. Ophthalmology. 2002;109(5):920-927.

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

4. 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.

5. Chi SC, Kang YN, Huang YM. Efficacy and safety profile of intravitreal dexamethasone implant versus antivascular endothelial growth factor treatment in diabetic macular edema: a systematic review and meta-analysis. Sci Rep. 2023;13(1):7428.

6. 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.

7. Diabetic Retinopathy Clinical Research Network; Wells JA, Glassman AR, Ayala AR, Jampol LM, et al. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. N Engl J Med. 2015;372(13):1193-203.

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

9. Heier JS, Khanani AM, Quezada Ruiz C, et al. Efficacy, durability, and safety of intravitreal faricimab up to every 16 weeks for neovascular age-related macular degeneration (TENAYA and LUCERNE): two randomised, double-masked, phase 3, non-inferiority trials. Lancet. 2022;399(10326):729-740.

10. Ferro Desideri L, Traverso CE, Nicolò M, Munk MR. Faricimab for the treatment of diabetic macular edema and neovascular age-related macular degeneration. Pharmaceutics. 2023;15(5):1413.

11. Brown DM, Boyer DS, Do DV, et al. Intravitreal aflibercept 8 mg in diabetic macular oedema (PHOTON): 48-week results from a randomised, double-masked, non-inferiority, phase 2/3 trial. Lancet. 2024;403(10432):1153-1163.

12. Gale RP, Peto T, Talks J, et al. Real-world use of Faricimab to treat DME patients in the UK (FARWIDE Study). Presented at the American Society of Retina Specialists Annual Meeting; July 28-August 1, 2023; Seattle, Washington.

13. Tabano D, Garmo V, Leng T, et al. Early Treatment patterns and outcomes in patients with diabetic macular edema treated with faricimab: the FARETINA-DME study. Presented at the American Society of Retina Specialists Annual Meeting; July 28-August 1, 2023; Seattle, Washington.