Abstract
Purpose:
This article compares 2-mg intravitreal triamcinolone (IVT) and 0.7-mg dexamethasone (DEX) implant for the treatment of diabetic macular edema in eyes that had a suboptimal response to antivascular endothelial growth factor therapy.
Methods:
A single-center, retrospective review was conducted of patients receiving either IVT between January 1, 2013, and January 1, 2018, or patients receiving DEX between October 1, 2015, and January 1, 2018. Visual acuity and central macular thickness (CMT) were recorded at visit of first injection and all subsequent visits.
Results:
Twenty-five eyes were included in the DEX group and 32 eyes were included in the IVT group. Change in vision from baseline was similar between DEX and IVT at 6-month follow-up (1.1 lines vs 2.3 lines, respectively; P = .24). Mean decrease in CMT from baseline was not different at 6-month follow-up (DEX: 120 µm vs IVT: 185 µm; P = .17).
Conclusions:
DEX and 2-mg IVT both achieved improvement in vision and CMT with no significant differences between treatment groups at 6-month follow-up.
Keywords: dexamethasone, diabetic macular edema, intravitreal steroids, triamcinolone
Introduction
Prolonged diabetic macular edema (DME) remains an important cause of vision loss in patients with diabetes. 1,2 Current treatment options include focal laser photocoagulation, intravitreal antivascular endothelial growth factor (anti-VEGF) injections, and intravitreal steroid injections. 3 Treatment with an intravitreal anti-VEGF agent typically is first-line therapy for center-involving DME. 4,5 Corticosteroids can be used as first-line therapy, 6,7 but more often are used in eyes that have a suboptimal response to anti-VEGF agents alone. 8 -10 Although an intravitreal dexamethasone (DEX) implant and intravitreal triamcinolone (IVT) reduce DME in eyes that have had a suboptimal response to anti-VEGF therapy, 8 -10 few studies have examined the efficacy of IVT at a 2-mg dose in this setting, and no prior study has compared the 2 agents. The purpose of this study is to compare visual and anatomic outcomes of eyes with a suboptimal response to anti-VEGF therapy for DME that were treated with either a 0.7-mg DEX implant or 2-mg IVT.
Methods
Inclusion and Exclusion Criteria
This study was a single-institution, retrospective review of patients receiving either a 0.7-mg DEX implant from October 1, 2015, to January 30, 2018, or 2-mg IVT from January 1, 2013, to January 30, 2018, for DME. All patients had a suboptimal response to treatment with anti-VEGF injections. Suboptimal response to treatment with anti-VEGF alone was defined as a central macular thickness (CMT) greater than 300 µm as measured using spectral-domain optical coherence tomography (Heidelberg Engineering). A minimum of 3 months’ follow-up after first treatment with DEX or IVT was required for inclusion. Patients receiving an anti-VEGF injection less than 28 days before first injection or at any point during the follow-up period were excluded. Patients receiving any other intravitreal, periocular, or systemic corticosteroid other than DEX or IVT within 3 months before first DEX or IVT injection or during the 6-month follow-up period were excluded. Visual acuity (VA), CMT, and intraocular pressure (IOP) were recorded at the time of injection and at all follow-up visits up to 6 months after first DEX or IVT.
Intravitreal Injection Technique
An intravitreal implant of 0.7-mg DEX (Ozurdex, Allergan Inc) was administered with a 22-gauge needle inserted 3.5 to 4.0 mm from the limbus. An injection of 2-mg IVT (Triesence, Alcon Laboratories) was performed with a 27- or 30-gauge needle inserted 3.5 to 4.0 mm from the limbus.
Outcomes
The primary outcome of this study was mean change in VA from baseline. Secondary outcomes included change in CMT from baseline, ocular hypertension (OHT; defined as IOP ≥ 24 mm Hg) during the minimum 3-month follow-up period, and cataract extraction within 24 months of first steroid injection. Hemoglobin A1c (HbA1c) was recorded at the visit of the first injection. A Snellen eye chart was used to determine VA. Snellen VA values were converted to logarithm of the minimum angle of resolution (logMAR) for analysis. Patients with VA classified as counting fingers were assigned a value of 2.3. 9 IOP was measured using a Tono-Pen XL tonometer (Reichert Inc), with confirmation of IOP greater than or equal to 24 mm Hg with Goldmann applanation tonometry (Haag-Streit, Switzerland). CMT was measured with spectral-domain optical coherence tomography (Topcon Corporation). Data were recorded at 1-month, 3-month, and 6-month follow-up visits, when available, after first DEX or IVT. Retreatment with intraocular steroids was performed on an as-needed basis by the treating physician.
Results
Demographics
Twenty-five eyes from 20 patients received DEX and 32 eyes from 26 patients received IVT and were included in the study. The mean age of patients receiving DEX was 66.4 years (range, 42.6-88.1 years) vs 63.7 years (range, 32.4-82.4 years) in patients receiving IVT (P = .36). Eighteen eyes (72.0%) in the DEX group and 24 eyes (75.0%) in the IVT group (P = .80) were pseudophakic at the time of the first injection.
Mean follow-up duration was 24.2 months (range, 4.2-40.1 months) in patients receiving DEX and 22.7 months (range, 3.3-56.9 months) in patients receiving IVT (P = .69). Twenty-four eyes (96.0%) in the DEX group compared with 25 eyes (78.1%) in the IVT group had at least 6 months’ follow-up (P = .07). Fifteen eyes (55.6%) in the DEX group received retreatment within the 6-month follow-up period compared with 14 eyes (43.8%) in the IVT group (P = .44). The mean time to retreatment was 4.0 months (range, 1.9-5.4 months) in the DEX group compared with 3.5 months (range, 2.3-5.0 months) in the IVT group (P = .18).
All eyes had a suboptimal response to previous treatment with anti-VEGF injection. The mean time between last anti-VEGF therapy and first DEX implant injection was 4.2 months (range, 0.93-28.7 months) compared with 4.7 months (range, 0.93-49.2 months) between last anti-VEGF therapy and first IVT (P = .82). The mean number of prior anti-VEGF injections was 6.3 (range, 1-25) in the eyes in the DEX group compared with 6.7 (range, 2-24) in the IVT group (P = .81). Twenty-one eyes (80.7%) received 3 or more anti-VEGF injections before receiving DEX compared with 20 eyes (80.0%) in the IVT group (P > .99). Seven eyes in the DEX group (28.0%) received prior focal laser photocoagulation compared with 4 eyes (14.5%) in the IVT group (P = .18). Mean HbA1c at baseline was 7.7 in the DEX group and 7.1 in the IVT group (P = .02). No eyes in the DEX group had previously received IVT and no eyes in the IVT group had previously received DEX.
Visual Acuity
Within the DEX group, the mean improvement in VA from baseline was significant at all follow-up visits: 1 month: 0.7 lines (P = .04); 3 months: 0.7 lines (P = .03); and 6 months: 1.1 lines (P = .006). Within the IVT group, the mean gain in VA from baseline was also significant at all follow-up visits: 1 month: 1.7 lines (P = .04); 3 months: 2.7 lines (P = .01); and 6 months: 2.3 lines (P = .03).
VA at baseline in the DEX group was logMAR 0.65 (Snellen equivalent, ∼20/90) vs logMAR 0.92 (Snellen, ∼20/170) in the IVT group (P = .13). Mean VA and improvement in VA from baseline are reported in Table 1 and shown in Figure 1.
Table 1.
Visual Acuity After 0.7-mg Intravitreal Dexamethasone and 2-mg Intravitreal Triamcinolone Acetonide.
| Visit | Agent | Average VA logMAR (Approximate Snellen Equivalent) | Average logMAR Lines Gained From Baseline | P |
|---|---|---|---|---|
| Baseline | DEX | 0.65 (20/90) | .13 | |
| IVT | 0.92 (20/170) | |||
| 1 mo | DEX | 0.58a (20/80) | 0.7 | .24 |
| IVT | 0.73a (20/110) | 1.7 | ||
| 3 mo | DEX | 0.58a (20/80) | 0.7 | .06 |
| IVT | 0.66a (20/90) | 2.7 | ||
| 6 mo | DEX | 0.55a (20/70) | 1.1 | .24 |
| IVT | 0.62a (20/80) | 2.3 |
Abbreviations: DEX, intravitreal dexamethasone implant (0.7 mg); IVT, intravitreal triamcinolone acetonide (2 mg); logMAR, logarithm of the minimum angle of resolution; VA, visual acuity.
aP < .05 within group when compared with baseline.
Figure 1.
Mean visual acuity at baseline, and at 1-month, 3-month, and 6-month follow-up for 0.7-mg intravitreal dexamethasone implant (DEX) and 2-mg intravitreal triamcinolone (IVT). LogMAR indicates logarithm of the minimum angle of resolution. *P < .05 within group when compared with baseline; error bars show 95% CI of the mean.
Between treatment groups, there was no significant difference in the increase in lines of vision from baseline at any follow-up points (1 month: DEX 0.7 vs IVT 2.7, P = .24; 3 months: DEX 0.7 vs IVT 1.7, P = .06; 6 months: DEX 1.1 vs IVT 2.3, P = .24).
Central Macular Thickness
Mean CMT at baseline was 467 µm in the DEX group and 549 µm in the IVT group (P = .07). Mean CMT and change in CMT from baseline are reported in Table 2 and shown in Figure 2.
Table 2.
Central Macular Thickness After 0.7-mg Intravitreal Dexamethasone Implant and 2-mg Intravitreal Triamcinolone Acetonide.
| Visit | Agent | Average Central Macular Thickness, μm | Average Decrease in CMT From Baseline, μm | P |
|---|---|---|---|---|
| Baseline | DEX | 467 | – | .07 |
| IVT | 549 | – | ||
| 1 mo | DEX | 333a | 140 | .048 |
| IVT | 325a | 230 | ||
| 3 mo | DEX | 348a | 119 | .41 |
| IVT | 374a | 158 | ||
| 6 mo | DEX | 346a | 120 | .17 |
| IVT | 349a | 185 |
Abbreviations: CMT, central macular thickness, DEX, intravitreal dexamethasone implant (0.7 mg); IVT, intravitreal triamcinolone acetonide (2 mg); logMAR, logarithm of the minimum angle of resolution.
aP < .001 within group when compared with baseline.
Figure 2.
Mean central macular thickness at baseline, and at 1-month, 3-month, and 6-month follow-up for 0.7-mg intravitreal dexamethasone implant (DEX) and 2-mg intravitreal triamcinolone (IVT). *P < .001 within group when compared with baseline; error bars show 95% CI of the mean.
In both the DEX and IVT groups, the mean decrease in CMT from baseline was significant (P < .001) at all follow-up visits.
The mean CMT at 1 month was similar between the DEX group (333 µm) and IVT group (325 µm; P = .96), although the CMT decreased significantly more during this time period in the IVT group (230 µm) compared with the DEX group (140 µm; P = .048). At 6 months’ follow-up, there was no significant difference in the mean change in CMT between groups (DEX: 120 µm, IVT: 185 µm; P = .17).
Ocular Hypertension
OHT, which was defined as a measured IOP greater than 24 mm Hg at any follow-up visit, occurred in 2 eyes (8.0%) in the DEX group compared with 4 eyes (12.5%) in the IVT group (P = .69). All eyes were successfully treated with observation or topical ocular antihypertensive medication. No eyes in either group required surgical intervention to lower IOP.
Lens Status
In the overall cohort, mean baseline VA was logMAR 0.77 (Snellen, ∼20/120) in 42 pseudophakic eyes and logMAR 0.89 (Snellen, ∼20/160) in 15 phakic eyes (P = .58). At 6 months’ follow-up, pseudophakic eyes gained a mean of 1.9 lines of Snellen VA, whereas phakic eyes gained a mean of 1.4 lines (P = .69).
In the DEX group, 3 of 7 (42.9%) phakic eyes had cataract extraction within 24 months of the first injection compared with 4 of 8 (50.0%) phakic eyes in the IVT group (P > .99). Mean time between steroid injection and cataract extraction was 14.8 months (range, 2.9-22.9 months).
Conclusions
Our study found that in eyes with DME that had a suboptimal response to anti-VEGF therapy, 0.7-mg DEX and 2-mg IVT both achieved significant improvement in VA as well as in CMT at 1-, 3-, and 6-month follow-up. Prior studies of intraocular steroid treatment of DME have demonstrated varying results; however, most show improvement at 3 to 6 months. 8,9,11,12 In the present study, at 6 months after initiation of steroid treatment, VA improved by a mean of 1.1 lines and mean CMT improved by 120 µm in the DEX group. In the IVT group, VA improved by a mean of 2.4 lines and mean CMT improved by 185 µm over the same time period. These improvements in VA and CMT were not significantly different between the treatment groups.
In our study, the mean VA and CMT were similar between treatment groups at baseline and all follow-up intervals. Although the mean change in CMT was significantly greater in the IVT group compared with the DEX group at 1 month (230 µm vs 140 µm), the similarity in mean CMT (325 µm vs 333 µm) and mean VA (20/110 vs 20/80) at 1-month follow-up and the approximately 80-µm difference in CMT at baseline between groups (IVT: 549 µm vs DEX: 467 µm) suggest that this difference is not clinically significant. Furthermore, the difference in change in CMT from baseline is no longer significant at 3- and 6-month follow-up. Another factor that may have contributed to the early difference in CMT improvement between groups is the disparity in glycemic control. The higher HbA1c in the DEX group at baseline may have been associated with more severe pathology and could have contributed to slower CMT improvement.
The rate of OHT in our study (IOP ≥ 24 mm Hg) was found to be 8.0% in the DEX group and 12.5% in the IVT group. All cases of OHT were successfully managed with observation or IOP-lowering drops. Our rates of OHT are similar to rates reported in the literature, although there are limited studies of the 2-mg dose of IVT. 6,13,14
All patients in this study had a suboptimal response to anti-VEGF treatment and were switched to treatment with DEX or IVT. The point at which to switch from anti-VEGF therapy to intravitreal corticosteroids is debated. Whereas some experts switch after 3 to 6 treatments with a suboptimal response, other studies have suggested not switching at all. 15 -18 In our study, approximately 80% of eyes in both groups received at least 3 anti-VEGF treatments before switching (mean number of injections before switching, 6.5; range, 1-25). Although our study cannot comment on the optimal duration of a trial of anti-VEGF therapy, our results suggest that switching to either IVT or DEX can help eyes with a suboptimal response to treatment with anti-VEGF.
Our study also sought to demonstrate the efficacy of 2-mg IVT in the treatment of DME. Although a 4-mg dose of IVT is more commonly used, several studies have found low-dose triamcinolone (1 or 2 mg) to be similarly effective with a lower risk of glaucoma and cataract development. 19,20 Improvement in both VA and CMT with 2-mg IVT was comparable with 0.7-mg DEX.
When deciding between DEX and IVT for treatment, several factors including physician familiarity and comfort with each treatment may guide medication choice. Cost is also another consideration because DEX is more expensive than IVT. Finally, DEX is contraindicated in eyes that have zonule disruption, making IVT the safer option for these patients.
Strengths of our study include an isolation of the effects of treatment by excluding patients with any overlapping intravitreal or periocular steroid or anti-VEGF treatment. All eyes in our study had a minimum of 3 months’ follow-up, with approximately 90% of eyes having 6 months’ follow-up. Weaknesses of our study include its retrospective nature, as well as a limited sample size, which may have resulted in insufficient power to detect differences between treatments. There was a variable anti-VEGF treatment before intraocular steroid, and choice of steroid was at the discretion of the treating physician. Furthermore, the dates of inclusion are different between the IVT and DEX groups. The study period for the DEX group was 2.3 years compared with 5.0 years in the IVT group. Given our practice’s more frequent usage of DEX, the IVT group required a larger inclusion period to capture similarly sized study populations. We did not find evidence that the difference in inclusion dates affected outcomes. Another limitation of our study may be the duration of follow-up because our study compares outcomes only up to 6 months. It is possible that a difference in efficacy and safety between DEX and IVT may be seen with longer follow-up.
In summary, we found that both 0.7-mg DEX and 2-mg IVT improved VA as well as CMT in eyes with DME that had suboptimal response to anti-VEGF therapy. When compared with baseline, no significant difference was found in either VA or CMT between the treatment with DEX and IVT at 3- and 6-month follow-up visits. Although future research may delineate possible differences in these 2 treatments, both medications remain valuable tools for the management of DME.
Footnotes
Ethical Approval: This study received approval from the institutional review board of Wills Eye Hospital and adheres to the tenets of the Declaration of Helsinki.
Statement of Informed Consent: Written consent was not obtained because patient data were unidentifiable.
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
ORCID iD: Turner D. Wibbelsman, BS 
https://orcid.org/0000-0003-4046-6553
References
- 1. Ciulla TA, Amador AG, Zinman B. Diabetic retinopathy and diabetic macular edema: pathophysiology, screening, and novel therapies. Diabetes Care. 2003;26(9):2653–2664. doi:10.2337/diacare.26.9.2653 [DOI] [PubMed] [Google Scholar]
- 2. Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study report number 1. Early Treatment Diabetic Retinopathy Study Research Group. Arch Ophthalmol. 1985;103(12):1796–1806. doi:10.1001/archopht.1985.01050120030015 [PubMed] [Google Scholar]
- 3. Wang W, Lo ACY. Diabetic retinopathy: pathophysiology and treatments. Int J Mol Sci. 2018;19(6):1816. doi:10.3390/ijms19061816 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4. Diabetic Retinopathy Clinical Research Network, Elman MJ, Aiello LP, et al. Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology. 2010;117(6):1064–1077.e35. doi:10.1016/j.ophtha.2010.02.031 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. Cheung N, Wong IY, Wong TY. Ocular anti-VEGF therapy for diabetic retinopathy: overview of clinical efficacy and evolving applications. Diabetes Care. 2014;37(4):900–905. doi:10.2337/dc13-1990 [DOI] [PubMed] [Google Scholar]
- 6. Boyer DS, Yoon YH, Belfort R., Jr et al. ; Ozurdex MEAD Study Group. Three-year, randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with diabetic macular edema. Ophthalmology. 2014;121(10):1904–1914. doi:10.1016/j.ophtha.2014.04.024 [DOI] [PubMed] [Google Scholar]
- 7. Escobar-Barranco JJ, Pina-Marín B, Fernández-Bonet M. Dexamethasone implants in patients with naive or refractory diffuse diabetic macular edema. Ophthalmologica. 2015;233(3-4):176–185. doi:10.1159/000371770 [DOI] [PubMed] [Google Scholar]
- 8. Iglicki M, Busch C, Zur D, et al. Dexamethasone implant for diabetic macular edema in naive compared with refractory eyes: the International Retina Group real-life 24-month multicenter study. The IRGREL-DEX study. Retina. 2019;39(1):44–51. doi:10.1097/IAE.0000000000002196 [DOI] [PubMed] [Google Scholar]
- 9. Pacella F, Romano MR, Turchetti P, et al. An eighteen-month follow-up study on the effects of intravitreal dexamethasone implant in diabetic macular edema refractory to anti-VEGF therapy. Int J Ophthalmol. 2016;9(10):1427–1432. doi:10.18240/ijo.2016.10.10 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10. Pacella F, Ferraresi AF, Turchetti P, et al. Intravitreal injection of Ozurdex((R)) implant in patients with persistent diabetic macular edema, with six-month follow-up. Ophthalmol Eye Dis. 2016;8:11–16. doi:10.4137/OED.S38028 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11. Unsal E, Eltutar K, Sultan P, Erkul SO, Osmanbasoglu OA. Efficacy and safety of intravitreal dexamethasone implants for treatment of refractory diabetic macular edema. Korean J Ophthalmol. 2017;31(2):115–122. doi: 10.3341/kjo.2017.31.2.115 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12. Jeon S, Lee WK. Effect of intravitreal triamcinolone in diabetic macular edema unresponsive to intravitreal bevacizumab. Retina. 2014;34(8):1606–1611. doi:10.1097/IAE.0000000000000109 [DOI] [PubMed] [Google Scholar]
- 13. Haller JA, Bandello F, Belfort R, Jr, et al. Randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with macular edema due to retinal vein occlusion. Ophthalmology. 2010;117(6):1134–1146.e3. doi:10.1016/j.ophtha.2010.03.032 [DOI] [PubMed] [Google Scholar]
- 14. Storey PP, Obeid A, Pancholy M, et al. Ocular hypertension after intravitreal injection of 2 mg triamcinolone. Retina. 2020;40(1):75–79. doi:10.1097/IAE.0000000000002361 [DOI] [PubMed] [Google Scholar]
- 15. Regillo CD, Callanan DG, Do DV, et al. Use of corticosteroids in the treatment of patients with diabetic macular edema who have a suboptimal response to anti-VEGF: recommendations of an expert panel. Ophthalmic Surg Lasers Imaging Retina. 2017;48(4):291–301. doi:10.3928/23258160-20170329-03 [DOI] [PubMed] [Google Scholar]
- 16. Busch C, Zur D, Fraser-Bell S. et al. ; International Retina Group. Shall we stay, or shall we switch? Continued anti-VEGF therapy versus early switch to dexamethasone implant in refractory diabetic macular edema. Acta Diabetol. 2018;55(8):789–796. doi:10.1007/s00592-018-1151-x [DOI] [PubMed] [Google Scholar]
- 17. Bressler NM, Beaulieu WT, Maguire MG. et al. ; Diabetic Retinopathy Clinical Research Network. Early response to anti-vascular endothelial growth factor and two-year outcomes among eyes with diabetic macular edema in Protocol T. Am J Ophthalmol. 2018;195:93–100. doi:S0002-9394(18)30413-6 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18. Maturi RK, Glassman AR, Liu D. et al. ; Diabetic Retinopathy Clinical Research Network. Effect of adding dexamethasone to continued ranibizumab treatment in patients with persistent diabetic macular edema: a DRCR Network phase 2 randomized clinical trial. JAMA Ophthalmol. 2018;136(1):29–38. doi:10.1001/jamaophthalmol.2017.4914 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19. Hauser D, Bukelman A, Pokroy R, et al. Intravitreal triamcinolone for diabetic macular edema: comparison of 1, 2, and 4 mg. Retina. 2008;28(6):825–830. doi:10.1097/IAE.0b013e318165767e [DOI] [PubMed] [Google Scholar]
- 20. 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.e10. doi:10.1016/j.ophtha.2008.06.015 [DOI] [PMC free article] [PubMed] [Google Scholar]