Anti-VEGF Therapy in Diabetic Retinopathy: A Synthesis of Efficacy, Durability, and a Clinical Decision-Making Framework in the Context of Developing Countries
DOI:
https://doi.org/10.38035/dhps.v4i1.3850Keywords:
Diabetic Retinopathy, Anti-VEGF, Diabetic Macular Edema, Treatment Durability, Developing CountriesAbstract
Diabetic retinopathy is a leading cause of preventable blindness in working-age populations, with vascular endothelial growth factor (VEGF) playing a central role in its progression. This critical narrative review aims to synthesize comparative evidence on the efficacy and durability of anti-VEGF agents and to formulate a contextual clinical decision-making framework for developing countries, particularly Indonesia. A literature search through PubMed/MEDLINE, Google Scholar, and ClinicalTrials.gov identified 143 articles; after stepwise screening with qualitative appraisal based on study design, sample size, and clinical relevance, 40 articles were included. Findings show that aflibercept demonstrated meaningful superiority in patients with poor baseline visual acuity of 20/50 or worse (approximately 2.7 ETDRS letters compared to bevacizumab, PROTOCOL T), while all three major agents yielded comparable outcomes at better baseline vision. Faricimab offered clinical durability up to 16 weeks in 53% of patients (YOSEMITE/RHINE). Approximately 30 to 40% of patients exhibit inadequate response, classifiable as primary non-response or secondary loss of response, each carrying distinct therapeutic implications. Optimal agent selection requires stratification by baseline visual acuity, durability profile, and cost-effectiveness considerations within Indonesia's National Health Insurance (JKN) system. Prospective research in the Indonesian population remains an urgent priority.
References
Adamis, A. P., Aiello, L. P., & D’Amato, R. A. (1999). Angiogenesis and ophthalmic disease. Angiogenesis, 3(1), 9–14. https://doi.org/10.1023/a:1009004700358
Aiello, L. P., Avery, R. L., Arrigg, P. G., Keyt, B. A., Jampel, H. D., Shah, S. T., et al. (1994). Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy. New England Journal of Medicine, 331(22), 1480–1487. https://doi.org/10.1056/NEJM199412013312203
American Academy of Ophthalmology. (2020). Diabetic retinopathy preferred practice pattern. Ophthalmology, 127(1), 66–145. https://doi.org/10.1016/j.ophtha.2019.09.025
Amin, R., Pratama, R., Purwanita, P., & Calisanie, M. A. M. O. P. (2026a). Association of foveal avascular zone diameter with best-corrected visual acuity in diabetic retinopathy: A cross-sectional optical coherence tomography angiography study. Bioscmed, 10(8), 2764–2776. https://bioscmed.com/index.php/bsm/article/view/1659
Amin, R., Rahayu, R., Purwanita, P., & Calisanie, M. A. M. O. P. (2026b). Retinal neural layer thickness and contrast sensitivity in type 2 diabetes without clinical retinopathy: A cross-sectional study. Bioscmed, 10(7), 2637–2648. https://bioscmed.com/index.php/bsm/article/view/1660
Boyer, D. S., Yoon, Y. H., Belfort, R., Jr., Bandello, F., Maturi, R. K., Augustin, A. J., et al. (2014). Three-year, randomized, sham-controlled trial of dexamethasone intravitreal implant in diabetic macular edema. Ophthalmology, 121(10), 1904–1914. https://doi.org/10.1016/j.ophtha.2014.04.024
Bressler, S. B., Glassman, A. R., Almukhtar, T., Bressler, N. M., Ferris, F. L., Googe, J. M., et al. (2016). Five-year outcomes of ranibizumab with prompt or deferred laser versus laser or triamcinolone plus deferred ranibizumab for diabetic macular edema. American Journal of Ophthalmology, 164, 57–68. https://doi.org/10.1016/j.ajo.2015.12.025
Brownlee, M. (2005). The pathobiology of diabetic complications: A unifying mechanism. Diabetes, 54(6), 1615–1625. https://doi.org/10.2337/diabetes.54.6.1615
Campochiaro, P. A., Marcus, D. M., Awh, C. C., Regillo, C., Adamis, A. P., Bantseev, V., et al. (2019). The port delivery system with ranibizumab for neovascular age-related macular degeneration: Results from the randomized phase 2 Ladder clinical trial. Ophthalmology, 126(8), 1141–1154. https://doi.org/10.1016/j.ophtha.2019.03.036
Cheung, N., Mitchell, P., & Wong, T. Y. (2010). Diabetic retinopathy. Lancet, 376(9735), 124–136. https://doi.org/10.1016/S0140-6736(09)62124-3
Diabetic Retinopathy Clinical Research Network. (2014). Relationship of retinal thickness to diabetic retinopathy severity in eyes without center-involved diabetic macular edema. Retina, 34(9), 1742–1749. https://doi.org/10.1097/IAE.0000000000000151
Early Treatment Diabetic Retinopathy Study Research Group. (1985). Photocoagulation for diabetic macular edema: ETDRS report number 1. Archives of Ophthalmology, 103(12), 1796–1806. https://doi.org/10.1001/archopht.1985.01050120030015
Early Treatment Diabetic Retinopathy Study Research Group. (1991). Grading diabetic retinopathy from stereoscopic color fundus photographs: ETDRS report number 10. Ophthalmology, 98(5, Suppl.), 786–806. https://doi.org/10.1016/s0161-6420(13)38012-9
Ferrara, N., Gerber, H. P., & LeCouter, J. (2003). The biology of VEGF and its receptors. Nature Medicine, 9(6), 669–676. https://doi.org/10.1038/nm0603-669
Ferrara, N., Damico, L., Shams, N., Lowman, H., & Kim, R. (2006). Development of ranibizumab, an anti-vascular endothelial growth factor antigen binding fragment, as therapy for neovascular age-related macular degeneration. Retina, 26(8), 859–870. https://doi.org/10.1097/01.iae.0000242842.14624.e7
Fileta, J. B., Scott, I. U., & Flynn, H. W., Jr. (2014). Meta-analysis of infectious endophthalmitis after intravitreal injection of anti-vascular endothelial growth factor agents. Ophthalmic Surgery, Lasers and Imaging Retina, 45(2), 143–149. https://doi.org/10.3928/23258160-20140306-08
Gross, J. G., Glassman, A. R., Jampol, L. M., Inusah, S., Aiello, L. P., Antoszyk, A. N., et al. (2015). Panretinal photocoagulation vs intravitreous ranibizumab for proliferative diabetic retinopathy. JAMA, 314(20), 2137–2146. https://doi.org/10.1001/jama.2015.15217
Gross, J. G., Glassman, A. R., Liu, D., Sun, J. K., Antoszyk, A. N., Baker, C. W., et al. (2018). Five-year outcomes of panretinal photocoagulation vs intravitreous ranibizumab for proliferative diabetic retinopathy (PROTOCOL S). JAMA Ophthalmology, 136(10), 1138–1148. https://doi.org/10.1001/jamaophthalmol.2018.3255
Gulshan, V., Peng, L., Coram, M., Stumpe, M. C., Wu, D., Narayanaswamy, A., et al. (2016). Development and validation of a deep learning algorithm for detection of diabetic retinopathy. JAMA, 316(22), 2402–2410. https://doi.org/10.1001/jama.2016.17216
Hammes, H. P., Lin, J., Renner, O., Shani, M., Lundqvist, A., Betsholtz, C., et al. (2002). Pericytes and the pathogenesis of diabetic retinopathy. Diabetes, 51(10), 3107–3112. https://doi.org/10.2337/diabetes.51.10.3107
International Diabetes Federation. (2021). IDF diabetes atlas (10th ed.). International Diabetes Federation. https://doi.org/10.1016/j.diabres.2021.109119
Joussen, A. M., Poulaki, V., Le, M. L., Koizumi, K., Esser, C., Janicki, H., et al. (2004). A central role for inflammation in the pathogenesis of diabetic retinopathy. FASEB Journal, 18(12), 1450–1452. https://doi.org/10.1096/fj.03-1476fje
Kemenkes RI. (2018). Riset kesehatan dasar (Riskesdas) 2018. Badan Penelitian dan Pengembangan Kesehatan. https://doi.org/10.22435/bpk.v46i1.372
Khanani, A. M., Kothari, A., Warwick, A., Chien, J. L., Westenskow, P. D., Bhatt, N., et al. (2024). PRISM: Phase 1/2 study of 4D-150 intravitreal gene therapy for diabetic macular edema. Ophthalmology Retina. Advance online publication. https://doi.org/10.1016/j.oret.2024.01.020
Korobelnik, J. F., Do, D. V., Schmidt-Erfurth, U., Boyer, D. S., Holz, F. G., Heier, J. S., et al. (2014). Intravitreal aflibercept for diabetic macular edema. Ophthalmology, 121(11), 2247–2254. https://doi.org/10.1016/j.ophtha.2014.05.006
Korobelnik, J. F., Do, D. V., Schmidt-Erfurth, U., Boyer, D. S., Holz, F. G., Heier, J. S., et al. (2016). Intravitreal aflibercept for diabetic macular edema (VIVID-DME and VISTA-DME): Two-year results. Ophthalmology, 123(7), 1521–1529. https://doi.org/10.1016/j.ophtha.2016.03.008
Krentz, T., Bhatt, N., & Hussain, R. M. (2022). Real-world outcomes of anti-VEGF therapy for diabetic macular edema: A systematic review. Clinical Ophthalmology, 16, 1263–1276. https://doi.org/10.2147/OPTH.S356500
Mitchell, P., Bandello, F., Schmidt-Erfurth, U., Lang, G. E., Massin, P., Schlingemann, R. O., et al. (2011). The RESTORE study: Ranibizumab monotherapy or combined with laser versus laser monotherapy for diabetic macular edema. Ophthalmology, 118(4), 615–625. https://doi.org/10.1016/j.ophtha.2011.01.031
Nguyen, Q. D., Brown, D. M., Marcus, D. M., Boyer, D. S., Patel, S., Feiner, L., et al. (2012). Ranibizumab for diabetic macular edema: Results from two phase III randomized trials, RISE and RIDE. Ophthalmology, 119(4), 789–801. https://doi.org/10.1016/j.ophtha.2011.12.039
Papadopoulos, N., Martin, J., Ruan, Q., Rafique, A., Rosconi, M. P., Shi, E., et al. (2012). Binding and neutralization of vascular endothelial growth factor (VEGF) and related ligands by VEGF Trap, ranibizumab and bevacizumab. Angiogenesis, 15(2), 171–185. https://doi.org/10.1007/s10456-011-9249-6
Pokroy, R., Desai, U. R., Du Toit, N., & Morrison, J. C. (2011). Bevacizumab prior to vitrectomy for diabetic tractional retinal detachment. Eye, 25(8), 989–997. https://doi.org/10.1038/eye.2011.100
Schmidt-Erfurth, U., Garcia-Arumi, J., Bandello, F., Berg, K., Chakravarthy, U., Gerendas, B. S., et al. (2017). Guidelines for the management of diabetic macular edema by the European Society of Retina Specialists (EURETINA). Ophthalmologica, 237(4), 185–222. https://doi.org/10.1159/000458539
Stitt, A. W., Curtis, T. M., Chen, M., Medina, R. J., McKay, G. J., Jenkins, A., et al. (2016). The progress in understanding and treatment of diabetic retinopathy. Progress in Retinal and Eye Research, 51, 156–186. https://doi.org/10.1016/j.preteyeres.2015.08.001
Teo, Z. L., Tham, Y. C., Yu, M., Chee, M. L., Rim, T. H., Cheung, N., et al. (2021). Global prevalence of diabetic retinopathy and projection of burden through 2045. Ophthalmology, 128(11), 1580–1591. https://doi.org/10.1016/j.ophtha.2021.04.019
Virgili, G., Parravano, M., Evans, J. R., Gordon, I., & Lucenteforte, E. (2023). Anti-vascular endothelial growth factor for diabetic macular oedema: A network meta-analysis. Cochrane Database of Systematic Reviews, 2023(10), Article CD007419. https://doi.org/10.1002/14651858.CD007419.pub7
Wells, J. A., Glassman, A. R., Ayala, A. R., Jampol, L. M., Aiello, L. P., Antoszyk, A. N., et al. (2015). Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. New England Journal of Medicine, 372(13), 1193–1203. https://doi.org/10.1056/NEJMoa1414264
Wells, J. A., Glassman, A. R., Ayala, A. R., Jampol, L. M., Bressler, N. M., Bressler, S. B., et al. (2016). Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema: Two-year results from a comparative effectiveness randomized clinical trial. Ophthalmology, 123(6), 1351–1359. https://doi.org/10.1016/j.ophtha.2016.02.022
Wilkinson, C. P., Ferris, F. L., III, Klein, R. E., Lee, P. P., Agardh, C. D., Davis, M., et al. (2003). Proposed international clinical diabetic retinopathy and diabetic macular edema disease severity scales. Ophthalmology, 110(9), 1677–1682. https://doi.org/10.1016/S0161-6420(03)00475-5
Wykoff, C. C., Abreu, F., Adamis, A. P., Basu, K., Eichenbaum, D. A., Haskova, Z., et al. (2022). Efficacy, durability, and safety of intravitreal faricimab with extended dosing up to every 16 weeks in patients with diabetic macular oedema (YOSEMITE and RHINE). Lancet, 399(10326), 741–755. https://doi.org/10.1016/S0140-6736(22)00018-6
Wykoff, C. C., Bhatt, N. P., Brown, D. M., Boyer, D., Brown, K., Cunningham, M. A., et al. (2021). Efficacy and safety of intravitreal aflibercept in eyes with moderately severe to severe nonproliferative diabetic retinopathy (PROTOCOL W). JAMA Ophthalmology, 139(7), 701–712. https://doi.org/10.1001/jamaophthalmol.2021.0606
Yau, J. W., Rogers, S. L., Kawasaki, R., Lamoureux, E. L., Kowalski, J. W., Bek, T., et al. (2012). Global prevalence and major risk factors of diabetic retinopathy. Diabetes Care, 35(3), 556–564. https://doi.org/10.2337/dc11-1909
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