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The effect of combination therapy with intravitreal bevacizumab and topical timolol–dorzolamide eye drops on diabetic macular edema: a double-blind randomized controlled trial

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Abstract

Background

The mainstay of treatment in diabetic macular edema (DME) is intravitreal administration of anti-vascular endothelial growth factors (anti-VEGFs). Aqueous depressants may enhance the effects of anti-VEGF agents by prolonging their clearance via aqueous outflow.

Purpose

To compare the anatomical and functional outcomes of treatment with intravitreal bevacizumab (IVB) and topical timolol–dorzolamide versus IVB alone.

Method

In this randomized placebo-controlled clinical trial, patients with center-involving DME (ci-DME) and best corrected visual acuity (BCVA) of 20/30 or less were enrolled and randomly allocated to two treatment arms. One group received three monthly IVB injections and timolol–dorzolamide eye drops twice a day (IVB + TD group); the other group received three monthly IVB injections and artificial tear drops as placebo (IVB group). Patients underwent ophthalmic evaluations and macular optical coherence tomography scans at baseline and 1 month after the third injection.

Result

Forty-six eyes from 46 patients with ci-DME were recruited. There was no intergroup difference regarding age, gender distribution, diabetic retinopathy stage, glycemic indices, BCVA, central macular thickness (CMT), or intraocular pressure at baseline. BCVA was significantly improved in the IVB + TD group (0.46 ± 0.18 to 0.36 ± 0.18 logarithm of the minimum angle of resolution [logMAR], p = 0.002), in contrast to IVB group (0.40 ± 0.17 to 0.35 ± 0.22 logMAR, p = 0.113). Similarly, the IVB + TD group showed a significant reduction in CMT (p < 0.001), unlike the IVB group (p = 0.086); and the CMT change in the former was greater than in the latter (− 0.57 ± 57.67 vs. − 25.52 ± 68.02 μm, p = 0.033).

Conclusion

Our findings support the short-term effectiveness of topical timolol–dorzolamide as adjunctive therapy to IVB injections in managing center-involving DME in terms of anatomical and visual outcomes. Trial registration: Clinicaltrials.gov NCT05083689 (October 19, 2021).

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Data availability

The data supporting the findings of this study are available from the corresponding author upon reasonable request.

Code availability

Not applicable.

References

  1. Miller K, Fortun JA (2018) Diabetic macular edema: current understanding, pharmacologic treatment options, and developing therapies. The Asia-Pacific J Ophthalmol 7(1):28–35

    CAS  Google Scholar 

  2. Tan GS et al (2017) Diabetic macular oedema. Lancet Diabetes Endocrinol 5(2):143–155

    Article  CAS  PubMed  Google Scholar 

  3. Romero-Aroca P et al (2016) Diabetic macular edema pathophysiology: vasogenic versus inflammatory. J Diabetes Res 2016:2156273

    Article  PubMed  PubMed Central  Google Scholar 

  4. Wong TY et al (2018) Guidelines on diabetic eye care: the international council of ophthalmology recommendations for screening, follow-up, referral, and treatment based on resource settings. Ophthalmology 125(10):1608–1622

    Article  PubMed  Google Scholar 

  5. Schmidt-Erfurth U et al (2017) Guidelines for the management of diabetic macular edema by the european society of retina specialists (EURETINA). Ophthalmologica 237(4):185–222

    Article  PubMed  Google Scholar 

  6. Bakri SJ et al (2007) Pharmacokinetics of intravitreal bevacizumab (Avastin). Ophthalmology 114(5):855–859

    Article  PubMed  Google Scholar 

  7. Krohne TU et al (2008) Intraocular pharmacokinetics of bevacizumab after a single intravitreal injection in humans. Am J Ophthalmol 146(4):508–512

    Article  CAS  PubMed  Google Scholar 

  8. Moisseiev E et al (2014) Pharmacokinetics of bevacizumab after topical and intravitreal administration in human eyes. Graefes Arch Clin Exp Ophthalmol 252(2):331–337

    Article  CAS  PubMed  Google Scholar 

  9. Sridhar J et al (2016) Topical dorzolamide–timolol with intravitreous anti-vascular endothelial growth factor for neovascular age-related macular degeneration. JAMA ophthalmology 134(4):437–443

    Article  PubMed  Google Scholar 

  10. Terashima H et al (1996) Membrane-bound carbonic anhydrase activity in the rat corneal endothelium and retina. Jpn J Ophthalmol 40(2):142–153

    CAS  PubMed  Google Scholar 

  11. Casini G et al (2014) The β-adrenergic system as a possible new target for pharmacologic treatment of neovascular retinal diseases. Prog Retin Eye Res 42:103–129

    Article  CAS  PubMed  Google Scholar 

  12. Martini D et al (2011) Antiangiogenic effects of β2-adrenergic receptor blockade in a mouse model of oxygen-induced retinopathy. J Neurochem 119(6):1317–1329

    Article  CAS  PubMed  Google Scholar 

  13. Byeon SH et al (2009) Prolongation of activity of single intravitreal bevacizumab by adjuvant topical aqueous depressant (Timolol–Dorzolamide). Graefes Arch Clin Exp Ophthalmol 247(1):35–42

    Article  CAS  PubMed  Google Scholar 

  14. Falavarjani KG et al (2019) Efficacy of topical timolol eye drops for the treatment of diabetic macular edema. Ophthalmol Retina 3(6):538–539

    Article  PubMed  Google Scholar 

  15. Mirshahi A et al (2019) Efficacy of adjuvant topical timolol–dorzolamide with intravitreal bevacizumab injection in diabetic macular edema: a contralateral eye study. J Curr Ophthalmol 31(2):168–171

    Article  PubMed  PubMed Central  Google Scholar 

  16. Fazel F, Nikpour H, Pourazizi M (2020) Combination of intravitreal bevacizumab and topical dorzolamide versus intravitreal bevacizumab alone for diabetic macular edema: a randomized contralateral clinical trial. Biomed Res Int 2020:6794391

    Article  PubMed  PubMed Central  Google Scholar 

  17. Schulz KF et al (2010) CONSORT 2010 statement: updated guidelines for reporting parallel group randomised trials. BMJ 340:c332

    Article  PubMed  PubMed Central  Google Scholar 

  18. Brubaker RF et al (2000) Comparison of the efficacy of betaxolol–brinzolamide and timolol–dorzolamide as suppressors of aqueous humor flow in human subjects. Ophthalmology 107(2):283–287

    Article  CAS  PubMed  Google Scholar 

  19. Badawi AE et al (2021) Efficacy of topical dorzolamide 2% in diabetic cystoid macular edema. Int J Ophthalmol 14(9):1413–1418

    Article  MathSciNet  PubMed  PubMed Central  Google Scholar 

  20. Suzuki T et al (2013) Topical dorzolamide for macular edema in the early phase after vitrectomy and epiretinal membrane removal. Clin Ophthalmol 7:549–553

    Article  PubMed  PubMed Central  Google Scholar 

  21. Gao BB et al (2007) Extracellular carbonic anhydrase mediates hemorrhagic retinal and cerebral vascular permeability through prekallikrein activation. Nat Med 13(2):181–188

    Article  CAS  PubMed  Google Scholar 

  22. Weiwei Z, Hu R (2009) Targeting carbonic anhydrase to treat diabetic retinopathy: emerging evidences and encouraging results. Biochem Biophys Res Commun 390(3):368–371

    Article  PubMed  Google Scholar 

  23. Watanabe K, Chiou G (1983) Action mechanism of timolol to lower the intraocular pressure in rabbits. Ophthalmic Res 15(3):160–167

    Article  CAS  PubMed  Google Scholar 

  24. Stewart MW (2007) Predicted biologic activity of intravitreal bevacizumab. Retina 27(9):1196–1200

    Article  PubMed  Google Scholar 

  25. Lavine JA et al (2017) beta2-Adrenergic receptor antagonism attenuates CNV through inhibition of VEGF and IL-6 expression. Invest Ophthalmol Vis Sci 58(1):299–308

    Article  MathSciNet  CAS  PubMed  PubMed Central  Google Scholar 

  26. Lee JH et al (2019) Efficacy of adjuvant topical dorzolamide–timolol in patients with neovascular age-related macular degeneration refractory to anti-vascular endothelial growth factor therapy. Retina 39(10):1953–1958

    Article  CAS  PubMed  Google Scholar 

  27. Hsu J et al (2020) Effect of adjuvant topical dorzolamide–timolol vs placebo in neovascular age-related macular degeneration: a randomized clinical trial. JAMA Ophthalmol 138(5):560–567

    Article  PubMed  PubMed Central  Google Scholar 

  28. Obeid A et al (2021) Topical dorzolamide–timolol with intravitreous anti-vascular endothelial growth factor for retinal vein occlusion: a pilot study. Retin Cases Brief Rep 15(2):120–126

    Article  PubMed  Google Scholar 

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Acknowledgements

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Funding

Shahid Beheshti University of Medical Sciences provided institutional funding for this research

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Authors and Affiliations

  1. Ophthalmic Research Center, Research Institute for Ophthalmology and Vision Science, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Sahba Fekri, Ali Rabiei, Sadid Hooshmandi, Hosein Nouri & Seyed-Hossein Abtahi

  2. Labbafinejad Medical Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Sahba Fekri, Ali Rabiei, Sadid Hooshmandi & Seyed-Hossein Abtahi

  3. School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran

    Hosein Nouri

Authors
  1. Sahba Fekri
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  2. Ali Rabiei
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  4. Hosein Nouri
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  5. Seyed-Hossein Abtahi
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Contributions

SF conceptualized and designed this study; SF, AR, and SH conducted the interventions and acquired the data; AR, interpreted the data and drafted the manuscript; HN and SHA contributed to data interpretation and editing the manuscript. All authors approved the final version of the manuscript.

Corresponding authors

Correspondence to Ali Rabiei or Hosein Nouri.

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Competing interests

The authors declare that they have no competing interests.

Ethics approval

The Ethics Committee of Shahid Beheshti University of Medical Sciences approved the protocol of this study (ethics committee reference number: IR.SBMU.MSP.REC.1400.160).

Consent to participate

All patients signed informed consent letters for participating in this study.

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All patients signed informed consent letters regarding the publication of their anonymized data.

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Fekri, S., Rabiei, A., Hooshmandi, S. et al. 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 44, 101 (2024). https://doi.org/10.1007/s10792-024-03005-z

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