Diabetic Macular Edema Is Treatable, but Prevention Is Best

Diabetic macular edema (DME) is a leading cause of vision loss among adults worldwide.¹ This vision-threatening complication of diabetic retinopathy (DR) occurs when blood vessel damage allows blood and fluid to leak into the retina, the light-sensitive tissue at the back of the eye, leading to retinal swelling. Table 1^2,3 lists DME’s symptoms. Vascular endothelial growth factor (VEGF) inhibitors were the first biologics approved for its management.

DME affects approximately 21 million individuals worldwide, and ophthalmologists diagnose DME in more than 75,000 Americans annually. Approximately 30% of individuals with diabetes develop some magnitude of macular edema, and those with type 1 diabetes are more likely to be affected than those with type 2 diabetes. Advancing age is also a risk factor. Patients younger than 30 years who receive a diagnosis have a 10-year incidence of approximately 20%. In patients older than 30 years who receive a diagnosis, approximately 40% will develop DME in 10 years.^4,5

DR is strongly linked to hyperglycemia, which increases free radical formation, intracellular glucose levels, and Protein kinase C activation. Chronic hyperglycemia also promotes advanced glycation end-product formation, which precipitates diabetic eye disease. Black, Hispanic, and Indigenous individuals face increased risk for disease, and other risk factors include hypertension, hypercholesterolemia, and tobacco use.⁶

VEGF-A and ANG/TIE Pathways

In DME, increased vascular permeability, inflammation, and neovascularization destabilize vision. Results from clinical trials indicate major contributors to destabilization include VEGF-A and upregulated ANGPT2, which work synergistically within the angiopoietin-Tie (ANG/TIE) path-way. Usually, ANGPT1 binds to and phosphorylates the TIE2 receptor, supporting cell survival and vascular stability.⁶ Upregulated ANGPT2 works against the ANG/TIE pathway’s vascular stabilization effect and sensitizes blood vessels to VEGF-A. Hypoxic conditions enhance VEGF-A’s effects, induce translocation of hypoxia-inducible factor (HIF)-1 and HIF-2 to the nucleus, and promote VEGF transcription and other proangiogenic factors.⁶

Treatment Challenges

Intravitreal VEGF inhibitors (ie, aflibercept, bevacizumab [off-label], brolcizumab, ranibizumab) have been the gold standard for retinal diseases because they effectively reduce vision loss. By inhibiting VEGF’s physiologic effects, VEGF inhibitors reduce choroidal neovascularization. However, patients often struggle with monitoring requirements (eg, regular optical coherence tomography) and the frequency of intravitreal injections.^7-10 Intravitreal injections can also create an emotional burden. For some patients, the idea of intraocular injections can be a barrier and lead to significant trauma and nonadherence.^11,12 The average patient, who may also need a caregiver to help, commits almost 12 hours to 1 visit, from preparing to leave home to postappointment recovery (9 hours).¹³

Anti-VEGF monotherapy does not address fibrosis and inflammation. The ANG/TIE signaling pathway is a critical target that reduces vascular destabilization associated with inflammation and neovascularization. Intravitreal faricimab-svoa (Vabysmo) is the latest FDA-approved medication for DME, and it addresses both pathways.^6,14,15 Faricimab-svoa also requires frequent appointments for monitoring and treatment.¹⁵

Adverse Events

Intravitreal anti-VEGF therapy’s most common adverse events (AEs) include blurred vision, cataract, subconjunctival hemorrhage, eye pain, vitreous detachment, and vitreous floaters.^7,8 Increased intraocular pressure, infectious and noninfectious endophthalmitis, and retinal detachment are rare but possible.^7,8 The most common adverse reactions reported in patients receiving faricimab-svoa are cataract and subconjunctival hemorrhage.¹⁵

Although anti-VEGF therapies are effective and serious AEs are rare, patients often have concerns about consultation and injection frequency, out-of-pocket medical costs, and visual outcomes, with vision quality topping the list. All other things being equal, patients preferred treatment regimens involving fewer total clinic visits.¹⁶

Cost Concerns

Many patients with DME are Medicare beneficiaries. Part B covers 80% of physician-administered drugs, and patients must pay the remaining 20% of the medication’s allowable reimbursement and administration charges.¹⁷ Out-of-pocket costs and indirect costs, such as caregiver and patient absences from work, loss of employment, parking, and transportation, can accumulate rapidly.¹⁷ The mean annual out-of-pocket expenses associated with blindness in patients with moderate visual impairment were almost $14,000 in 2012. The out-of-pocket expenses were $16,000 for severe visual impairment and $24,000 for blindness.¹⁸

Implications for Pharmacists

Because DME is strongly associated with elevated blood sugar levels, pharmacists can encourage patients to address their diabetes aggressively as a preventive measure. Urging patients to monitor their hemoglobin A^1c levels closely and working with prescribers to overcome clinical inertia is critical. In addition, monitoring is prudent to ensure that dyslipidemia and hypertension are identified early, managed, and regularly controlled.

Once DME develops, pharmacists may think that they have little responsibility, because most medications are administered intravitreally in physicians’ offices. However, patients may have concerns about intravitreal injections, and knowledgeable pharmacy staff members can explain intravitreal injections and how to deal with any local discomfort afterward (Table 2¹⁹).

Conclusion

Prevention is the best approach to DME. Once DME develops, patients may need encouragement and support to remain adherent.

References

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2. Yeo NJY, Chan EJJ, Cheung C. Choroidal neovascularization: mechanisms of endothelial dysfunction. Front Pharmacol. 2019;10:1363. doi:10.3389/fphar.2019.01363
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4. Bhagat N, Grigorian RA, Tutela A, Zarbin MA. Diabetic macular edema: pathogenesis and treatment. Surv Ophthalmol. 2009;54(1):1-32. doi:10.1016/j.survophthal.2008.10.001
5. Li JQ, Welchowski T, Schmid M, et al. Prevalence, incidence and future projection of diabetic eye disease in Europe: a systematic review and meta-analysis. Eur J Epidemiol. 2020;35(1):11-23. doi:10.1007/s10654-019-00560-z
6. Joussen AM, Ricci F, Paris LP, Korn C, Quezada-Ruiz C, Zarbin M. Angiopoietin/Tie2 signalling and its role in retinal and choroidal vascular diseases: a review of preclinical data. Eye (Lond). 2021;35(5):1305-1316. doi:10.1038/s41433-020-01377-x
7. Beovu. Prescribing information. Novartis Pharmaceuticals; 2019. Accessed May 17, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/761125s000lbl.pdf
8. Eylea. Prescribing information. Regeneron Pharmaceuticals; 2011. Accessed May 17, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/125387lbl.pdf
9. Lucentis. Prescribing information. Genentech; 2014. Accessed May 17, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/125156s105lbl.pdf
10. Cabral T, Lima LH, Mello LGM, et al. Bevacizumab injection in patients with neovascular age-related macular degeneration increases angiogenic biomarkers. Ophthalmol Retina. 2018;2(1):31-37. doi:10.1016/j.oret.2017.04.004
11. Gale RP, Mahmood S, Devonport H, et al. Action on neovascular age-related macular degeneration (nAMD): recommendations for management and service provision in the UK hospital eye service. Eye (Lond). 2019;33(suppl 1):1-21. doi:10.1038/s41433-018-0300-3
12. Kapoor KG, Sim J. Spironolactone as an adjunctive treatment in neovascular age-related macular degeneration. Case Rep Ophthalmol. 2017;8(2):314-320. doi:10.1159/000475880
13. Prenner JL, Halperin LS, Rycroft C, Hogue S, Williams Liu Z, Seibert R. Disease burden in the treatment of age-related macular degeneration: findings from a time-and-motion study. Am J Ophthalmol. 2015;160(4):725-31.e1. doi:10.1016/j.ajo.2015.06.023
14. Hussain RM, Shaukat BA, Ciulla LM, Berrocal AM, Sridhar J. Vascular endothelial growth factor antagonists: promising players in the treatment of neovascular age-related macular degeneration. Drug Des Devel Ther. 2021;15:2653-2665. doi:10.2147/DDDT.S295223
15. Vabysmo. Prescribing information. Genentech; 2022. Accessed May 17, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/761235s000lbl.pdf
16. Ozdemir S, Finkelstein E, Lee JJ, et al. Understanding patient preferences in anti-VEGF treatment options for age-related macular degeneration. PLoS One. 2022;17(8):e0272301. doi:10.1371/journal.pone.0272301
17. Shah AR, Williams GA. Regulatory and economic considerations of retinal drugs. Dev Ophthalmol. 2016;55:376-380. doi:10.1159/000438965
18. Köberlein J, Beifus K, Schaffert C, Finger RP. The economic burden of visual impairment and blindness: a systematic review. BMJ Open. 2013;3(11):e003471. doi:10.1136/bmjopen-2013-003471
19. Intravitreal injections. American Society of Retina Specialists. Accessed April 22, 2023. https://www.asrs.org/patients/retinal-diseases/33/intravitreal-injections

About the Author

Jeannette Y. Wick, MBA, RPh, FASCP, is the director of pharmacy professional development in the Department of Pharmacy Practice at the University of Connecticut School of Pharmacy in Storrs.