Combination treatment strategies for diabetic macular edema: a systematic review and meta analysis
Main Article Content
Keywords
diabetic macular edema, anti-VEGF therapy, central macular thickness, best corrected visual acuity
Abstract
Introduction: Diabetic macular edema (DME) is a leading cause of vision loss in patients with diabetes. This meta-analysis compares the efficacy and safety of combination therapy and anti-VEGF monotherapy for DME treatment.
Method: A systematic literature search was conducted from January 2010 to December 2024, scanning through PubMed, Scopus, and Proquest databases. Trials comparing combination therapy and monotherapy in DME patients were included. This review adhered to PRISMA guidelines and risk of bias was assessed using Rob2 and ROBINS-I tools. Efficacy and safety were analyzed using standardized mean differences (SMD) and pooled in a forest plot using RevMan. PROSPERO registered (CRD420251028671)
Result: 12 RCTs and 1 non-randomized study involving 923 eyes. Combination therapy significantly reduces central macular thickness (CMT) compared to anti-VEGF monotherapy (SMD 0.49; 95% CI, 0.18-0.81; P <0.05; I² = 76%). Combination therapy showed a greater proportion of Best Corrected Visual Acuity (BCVA) reduction, although the difference was not statistically significant (SMD, 0.83; 95% CI, -0.03-1.70; P = 0.06; I² = 96%). Subgroup analysis indicated laser and anti-VEGF was effective combination in reducing CMT (SMD, 0.74; 95% CI, 0.18-0.81; P <0.05; I² = 83%). Diclofenac and Anti-VEGF also effective combination in reducing mean BCVA (SMD, 0.62; 95% CI, 0.25-0.99; P <0.05; I² = 0%). IOP elevation is reported in combination therapy includes corticosteroid.
Conclusion: Combination therapies (Laser or Diclofenac plus anti-VEGF) show superior efficacy in improving BCVA and reducing CMT in DME patients compared with monotherapy, with tolerable adverse events.
References
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10. Adán A, Cabrera F, Figueroa MS, Cervera E, Ascaso FJ, Udaondo P, et al. Clinical-Decision Criteria to Identify Recurrent Diabetic Macular Edema Patients Suitable for Fluocinolone Acetonide Implant Therapy (ILUVIEN®) and Follow-Up Considerations/Recommendations. Clin Ophthalmol [Internet]. 2020 [cited 2025 Jun 1];14:2091. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC7398681/
11. Downey L, Acharya N, Devonport H, Gale R, Habib M, Manjunath V, et al. Treatment choices for diabetic macular oedema: a guideline for when to consider an intravitreal corticosteroid, including adaptations for the COVID-19 era. BMJ Open Ophthalmol [Internet]. 2021 Apr 27 [cited 2025 Jun 1];6(1):e000696. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC8088120/
12. Mehta H, Hennings C, Gillies MC, Nguyen V, Campain A, Fraser-Bell S. Anti‐vascular endothelial growth factor combined with intravitreal steroids for diabetic macular oedema. Cochrane Database Syst Rev [Internet]. 2018 Apr 18 [cited 2025 Jun 9];2018(4):CD011599. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC6494419/
13. Abdel-Maboud M, Menshawy E, Bahbah EI, Outani O, Menshawy A. Intravitreal bevacizumab versus intravitreal triamcinolone for diabetic macular edema–Systematic review, meta-analysis and meta-regression. PLoS One [Internet]. 2021 Jan 1 [cited 2025 Jun 9];16(1):e0245010. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC7802957/
14. Whitcup SM, Cidlowski JA, Csaky KG, Ambati J. Pharmacology of Corticosteroids for Diabetic Macular Edema. Invest Ophthalmol Vis Sci [Internet]. 2018 Jan 1 [cited 2025 Jun 9];59(1):1. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC5961100/
15. Grad J, Hatamnejad A, Dadak R, Sodhi S, Pattathil N, Choudhry N. Anti-VEGF Monotherapy vs Anti-VEGF and Steroid Combination Therapy for Diabetic Macular Edema: A Meta-analysis. J Vitreoretin Dis [Internet]. 2024 Jan 1 [cited 2025 Jun 9];24741264241280596. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC11556321/
16. Zhou B, Liu H, Xiong F. Efficacy and safety of dexamethasone or triamcinolone in combination with anti-vascular endothelial growth factor therapy for diabetic macular edema: A systematic review and meta-analysis with trial sequential analysis. PLoS One [Internet]. 2025 Feb 1 [cited 2025 Jun 9];20(2). Available from: https://pubmed.ncbi.nlm.nih.gov/39919066/
17. Meng W, Li R, Xie X. Conbercept and Retinal Photocoagulation in the treatment of Diabetic Macular Edema. Pak J Med Sci [Internet]. 2019 Nov 1 [cited 2025 Jun 9];35(6):1493. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC6861463/
18. Huang C, Ji H, Han X. The Effectiveness of Conbercept Combined with Panretinal Photocoagulation vs. Panretinal Photocoagulation in the Treatment of Diabetic Retinopathy: A Meta-Analysis. J Ophthalmol [Internet]. 2021 [cited 2025 Jun 9];2021:5591719. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC8128542/
19. Bressler SB, Odia I, Glassman AR, Danis RP, Grover S, Robert Hampton G, et al. Changes in diabetic retinopathy severity when treating diabetic macular edema with ranibizumab DRCR.NET protocol I 5-year report. Retina [Internet]. 2018 [cited 2025 Jun 9];38(10):1896–904. Available from: https://journals.lww.com/retinajournal/fulltext/2018/10000/changes_in_diabetic_retinopathy_severity_when.2.aspx
20. Mitchell P, Bandello F, Schmidt-Erfurth U, Lang GE, Massin P, Schlingemann RO, et al. The RESTORE study: Ranibizumab monotherapy or combined with laser versus laser monotherapy for diabetic macular edema. Ophthalmology [Internet]. 2011 Apr 1 [cited 2025 Jun 9];118(4):615–25. Available from: https://www.aaojournal.org/action/showFullText?pii=S0161642011000649
21. Nidya Sandra M, Shabrina Y, Wahyu Widayanti T, Ekantini R, Supartoto A, Bayu Sasongko M. CENTRAL MACULAR THICKNESS AFTER COMBINED THERAPY OF BEVACIZUMAB INTRAVITREAL INJECTION AND TOPICAL DICLOFENAC COMPARED WITH BEVACIZUMAB INTRAVITREAL INJECTION IN DIABETIC MACULAR EDEMA. International Journal of Retina (IJRETINA) 2021 [Internet]. 4(2). Available from: https://doi.org/10.35479/ijretina.2021.v
22. Ghanbari H, Kianersi F, Sonbolestan SA, Abtahi MA, Akbari M, Abtahi ZA, et al. Intravitreal Diclofenac plus Bevacizumab versus Bevacizumab alone in treatment-naive diabetic macular edema: a randomized double-blind clinical trial. Int Ophthalmol [Internet]. 2017 Aug 1 [cited 2025 Jun 9];37(4):867–74. Available from: https://link.springer.com/article/10.1007/s10792-016-0335-z
23. Supanji S, Ramania W, Sandra MN, Agni AN, Suhardjo S, Ekantini R, et al. Efek Penambahan Natrium Diklofenak Topikal pada Terapi Injeksi Intravitreal Bevacizumab terhadap Perubahan Visus dan Tekanan Intraokular Pasien dengan Edema Makula Diabetika. Ophthalmologica Indonesiana [Internet]. 2023 Aug 31 [cited 2025 Jun 9];49(2):122–31. Available from: https://www.ophthalmologica-indonesiana.com/index.php/journal/article/view/100270
24. Sridhar J, Hsu J, Shahlaee A, Garg SJ, Spirn MJ, Fineman MS, et al. Topical Dorzolamide-Timolol With Intravitreous Anti-Vascular Endothelial Growth Factor for Neovascular Age-Related Macular Degeneration. JAMA Ophthalmol [Internet]. 2016 Apr 1 [cited 2025 Jun 9];134(4):437–43. Available from: https://pubmed.ncbi.nlm.nih.gov/26914218/
25. Harris A, Ciulla TA, Pratt LM, Rechtman E, Kagemann L, Piper HC, et al. The effects of dorzolamide on choroidal and retinal perfusion in non-exudative age related macular degeneration. Br J Ophthalmol [Internet]. 2003 Jun 1 [cited 2025 Jun 9];87(6):753. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC1771708/
26. Mirshahi A, Tadayoni R, Mohsenzadeh N, Saeidi Rezvani T, Abrishami M. Efficacy of adjuvant topical timolol–dorzolamide with intravitreal bevacizumab injection in diabetic macular edema: A contralateral eye study. J Curr Ophthalmol [Internet]. 2019 Jun 1 [cited 2025 Jun 9];31(2):168. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC6611985/
27. Mateos-Olivares M, García-Onrubia L, Valentín-Bravo FJ, González-Sarmiento R, Lopez-Galvez M, Pastor JC, et al. Rho-Kinase Inhibitors for the Treatment of Refractory Diabetic Macular Oedema. Cells [Internet]. 2021 Jul 1 [cited 2025 Jun 9];10(7). Available from: https://pubmed.ncbi.nlm.nih.gov/34359853/
2. Teo ZL, Tham YC, Yu M, Chee ML, Rim TH, Cheung N, et al. Global Prevalence of Diabetic Retinopathy and Projection of Burden through 2045: Systematic Review and Meta-analysis. Ophthalmology [Internet]. 2021 Nov 1 [cited 2025 Jun 9];128(11):1580–91. Available from: https://www.aaojournal.org/action/showFullText?pii=S0161642021003213
3. Tatsumi T. Current Treatments for Diabetic Macular Edema. Int J Mol Sci [Internet]. 2023 Jun 1 [cited 2025 Jun 9];24(11). Available from: https://pubmed.ncbi.nlm.nih.gov/37298544/
4. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ [Internet]. 2021 Mar 29 [cited 2025 Jun 1];372. Available from: https://www.bmj.com/content/372/bmj.n71
5. Ahmadieh H, Nourinia R, Hafezi-Moghadam A, Sabbaghi H, Nakao S, Zandi S, et al. Intravitreal injection of a Rho-kinase inhibitor (fasudil) combined with bevacizumab versus bevacizumab monotherapy for diabetic macular oedema: a pilot randomised clinical trial. British Journal of Ophthalmology [Internet]. 2019 Jul 1 [cited 2025 Jun 9];103(7):922–7. Available from: https://bjo.bmj.com/content/103/7/922
6. Fekri S, Rabiei A, Hooshmandi S, Nouri H, Abtahi SH. The effect of combination therapy with intravitreal bevacizumab and topical timolol-dorzolamide eye drops on diabetic macular edema: a double-blind randomized controlled trial. Int Ophthalmol [Internet]. 2024 Dec 1 [cited 2025 Jun 9];44(1). Available from: https://pubmed.ncbi.nlm.nih.gov/38376643/
7. Riazi-Esfahani M, Riazi-Esfahani H, Ahmadraji A, Karkhaneh R, Mahmoudi A, Roohipoor R, et al. Intravitreal bevacizumab alone or combined with 1 mg triamcinolone in diabetic macular edema: a randomized clinical trial. Int Ophthalmol [Internet]. 2018 Apr 1 [cited 2025 Jun 9];38(2):585–98. Available from: https://pubmed.ncbi.nlm.nih.gov/28349504/
8. Lim JW, Lee HK, Shin MC. Comparison of intravitreal bevacizumab alone or combined with triamcinolone versus triamcinolone in diabetic macular edema: A randomized clinical trial. Ophthalmologica [Internet]. 2012 Jan [cited 2025 Jun 9];227(2):100–6. Available from: https://www.researchgate.net/publication/51715189_Comparison_of_Intravitreal_Bevacizumab_Alone_or_Combined_with_Triamcinolone_versus_Triamcinolone_in_Diabetic_Macular_Edema_A_Randomized_Clinical_Trial
9. Neto HO, Regatieri C V., Nobrega MJ, Muccioli C, Casella AM, Andrade RE, et al. Multicenter, randomized clinical trial to assess the effectiveness of intravitreal injections of bevacizumab, triamcinolone, or their combination in the treatment of diabetic macular edema. Ophthalmic Surg Lasers Imaging Retina. 2017 Sep 1;48(9):734–40.
10. Adán A, Cabrera F, Figueroa MS, Cervera E, Ascaso FJ, Udaondo P, et al. Clinical-Decision Criteria to Identify Recurrent Diabetic Macular Edema Patients Suitable for Fluocinolone Acetonide Implant Therapy (ILUVIEN®) and Follow-Up Considerations/Recommendations. Clin Ophthalmol [Internet]. 2020 [cited 2025 Jun 1];14:2091. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC7398681/
11. Downey L, Acharya N, Devonport H, Gale R, Habib M, Manjunath V, et al. Treatment choices for diabetic macular oedema: a guideline for when to consider an intravitreal corticosteroid, including adaptations for the COVID-19 era. BMJ Open Ophthalmol [Internet]. 2021 Apr 27 [cited 2025 Jun 1];6(1):e000696. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC8088120/
12. Mehta H, Hennings C, Gillies MC, Nguyen V, Campain A, Fraser-Bell S. Anti‐vascular endothelial growth factor combined with intravitreal steroids for diabetic macular oedema. Cochrane Database Syst Rev [Internet]. 2018 Apr 18 [cited 2025 Jun 9];2018(4):CD011599. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC6494419/
13. Abdel-Maboud M, Menshawy E, Bahbah EI, Outani O, Menshawy A. Intravitreal bevacizumab versus intravitreal triamcinolone for diabetic macular edema–Systematic review, meta-analysis and meta-regression. PLoS One [Internet]. 2021 Jan 1 [cited 2025 Jun 9];16(1):e0245010. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC7802957/
14. Whitcup SM, Cidlowski JA, Csaky KG, Ambati J. Pharmacology of Corticosteroids for Diabetic Macular Edema. Invest Ophthalmol Vis Sci [Internet]. 2018 Jan 1 [cited 2025 Jun 9];59(1):1. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC5961100/
15. Grad J, Hatamnejad A, Dadak R, Sodhi S, Pattathil N, Choudhry N. Anti-VEGF Monotherapy vs Anti-VEGF and Steroid Combination Therapy for Diabetic Macular Edema: A Meta-analysis. J Vitreoretin Dis [Internet]. 2024 Jan 1 [cited 2025 Jun 9];24741264241280596. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC11556321/
16. Zhou B, Liu H, Xiong F. Efficacy and safety of dexamethasone or triamcinolone in combination with anti-vascular endothelial growth factor therapy for diabetic macular edema: A systematic review and meta-analysis with trial sequential analysis. PLoS One [Internet]. 2025 Feb 1 [cited 2025 Jun 9];20(2). Available from: https://pubmed.ncbi.nlm.nih.gov/39919066/
17. Meng W, Li R, Xie X. Conbercept and Retinal Photocoagulation in the treatment of Diabetic Macular Edema. Pak J Med Sci [Internet]. 2019 Nov 1 [cited 2025 Jun 9];35(6):1493. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC6861463/
18. Huang C, Ji H, Han X. The Effectiveness of Conbercept Combined with Panretinal Photocoagulation vs. Panretinal Photocoagulation in the Treatment of Diabetic Retinopathy: A Meta-Analysis. J Ophthalmol [Internet]. 2021 [cited 2025 Jun 9];2021:5591719. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC8128542/
19. Bressler SB, Odia I, Glassman AR, Danis RP, Grover S, Robert Hampton G, et al. Changes in diabetic retinopathy severity when treating diabetic macular edema with ranibizumab DRCR.NET protocol I 5-year report. Retina [Internet]. 2018 [cited 2025 Jun 9];38(10):1896–904. Available from: https://journals.lww.com/retinajournal/fulltext/2018/10000/changes_in_diabetic_retinopathy_severity_when.2.aspx
20. Mitchell P, Bandello F, Schmidt-Erfurth U, Lang GE, Massin P, Schlingemann RO, et al. The RESTORE study: Ranibizumab monotherapy or combined with laser versus laser monotherapy for diabetic macular edema. Ophthalmology [Internet]. 2011 Apr 1 [cited 2025 Jun 9];118(4):615–25. Available from: https://www.aaojournal.org/action/showFullText?pii=S0161642011000649
21. Nidya Sandra M, Shabrina Y, Wahyu Widayanti T, Ekantini R, Supartoto A, Bayu Sasongko M. CENTRAL MACULAR THICKNESS AFTER COMBINED THERAPY OF BEVACIZUMAB INTRAVITREAL INJECTION AND TOPICAL DICLOFENAC COMPARED WITH BEVACIZUMAB INTRAVITREAL INJECTION IN DIABETIC MACULAR EDEMA. International Journal of Retina (IJRETINA) 2021 [Internet]. 4(2). Available from: https://doi.org/10.35479/ijretina.2021.v
22. Ghanbari H, Kianersi F, Sonbolestan SA, Abtahi MA, Akbari M, Abtahi ZA, et al. Intravitreal Diclofenac plus Bevacizumab versus Bevacizumab alone in treatment-naive diabetic macular edema: a randomized double-blind clinical trial. Int Ophthalmol [Internet]. 2017 Aug 1 [cited 2025 Jun 9];37(4):867–74. Available from: https://link.springer.com/article/10.1007/s10792-016-0335-z
23. Supanji S, Ramania W, Sandra MN, Agni AN, Suhardjo S, Ekantini R, et al. Efek Penambahan Natrium Diklofenak Topikal pada Terapi Injeksi Intravitreal Bevacizumab terhadap Perubahan Visus dan Tekanan Intraokular Pasien dengan Edema Makula Diabetika. Ophthalmologica Indonesiana [Internet]. 2023 Aug 31 [cited 2025 Jun 9];49(2):122–31. Available from: https://www.ophthalmologica-indonesiana.com/index.php/journal/article/view/100270
24. Sridhar J, Hsu J, Shahlaee A, Garg SJ, Spirn MJ, Fineman MS, et al. Topical Dorzolamide-Timolol With Intravitreous Anti-Vascular Endothelial Growth Factor for Neovascular Age-Related Macular Degeneration. JAMA Ophthalmol [Internet]. 2016 Apr 1 [cited 2025 Jun 9];134(4):437–43. Available from: https://pubmed.ncbi.nlm.nih.gov/26914218/
25. Harris A, Ciulla TA, Pratt LM, Rechtman E, Kagemann L, Piper HC, et al. The effects of dorzolamide on choroidal and retinal perfusion in non-exudative age related macular degeneration. Br J Ophthalmol [Internet]. 2003 Jun 1 [cited 2025 Jun 9];87(6):753. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC1771708/
26. Mirshahi A, Tadayoni R, Mohsenzadeh N, Saeidi Rezvani T, Abrishami M. Efficacy of adjuvant topical timolol–dorzolamide with intravitreal bevacizumab injection in diabetic macular edema: A contralateral eye study. J Curr Ophthalmol [Internet]. 2019 Jun 1 [cited 2025 Jun 9];31(2):168. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC6611985/
27. Mateos-Olivares M, García-Onrubia L, Valentín-Bravo FJ, González-Sarmiento R, Lopez-Galvez M, Pastor JC, et al. Rho-Kinase Inhibitors for the Treatment of Refractory Diabetic Macular Oedema. Cells [Internet]. 2021 Jul 1 [cited 2025 Jun 9];10(7). Available from: https://pubmed.ncbi.nlm.nih.gov/34359853/