This study reports better visual outcomes and reduced treatment burden in naïve DME eyes compared to previously treated DME eyes, based on a large cohort of DME patients treated with the IDI in routine clinical care. The results of this study support the use of the IDI in early DME stages and provide further evidence of better IDI performance when used as first line therapy compared to its use as second line therapy, after previous failed intravitreal treatments.
Our real-world cohort of DME patients presented different demographics and baseline clinical characteristics from those reported in clinical trials, overall with a worse mean baseline VA [18–22] and CRT.[18–21] In our series, a significant number of study eyes were treated in routine clinical care with VA levels that fall outside the inclusion criteria used in the MEAD trial (33.5% of the study cohort, 6% with VA better than 0.4 logMAR and 27.5% with VA worse than 1.0 logMAR, as presented in Fig. 1). This data is of particular relevance, as reflects more closely the situation in which such a therapy is to be employed in routine clinical care: patients that require a therapeutic option even though they might not conform to the ideal profile, either in terms of specific disease related parameters, prior treatment failure or co-morbidities. In case of our cohort of previously treated eyes, their basal clinical characteristics are generally worse than those reported previously in real-world studies, particularly with lower baseline VA [22–28] and greater CRT.[23, 29] Moreover, more eyes had received prior treatment, particularly with anti-VEGF and/or IVTA, than the study cohorts in these previous series.[23, 24, 26, 28–30]
The overall results presented here are somehow comparable with those from previous smaller cohorts. Indeed, previous assessments of the effect of IDI on refractory and treatment-naive patients showed similar decreases in CRT and improvement in VA in both refractory and treatment-naive groups. Other real-life studies have also shown similar improvements in VA and CRT without serious adverse events, mainly in smaller series over shorter follow-up periods.[31–36] In our population of DME patients, IDI considerably improved the VA relative to baseline in both treatment-naive and previously treated patients, suggesting that IDI therapy offers benefits to both types of patient. Nevertheless, naive eyes maintained a better mean VA than previously treated eyes at all time points studied. A particularly significant improvement was observed in naïve patients during the first 3 months relative to previously treated eyes, suggesting they respond better in terms of VA, consistent with earlier data.[22, 24] Moreover, in our series the percentage of eyes with good VA levels was consistently higher in naïve eyes vs previously treated eyes at all study timepoints, as graphically presented in Fig. 1. Regarding anatomical changes, IDI treatment improves the CRT at all time points during the follow-up, both in treatment-naïve and previously treated eyes, with no significant differences between these subgroups. This discrepancy between functional and anatomical outcomes in DME has extensively been reported in previous studies, that suggest that retinal thinning may also be related with outer retinal layers atrophy preventing visual improvement, more common in chronic DME eyes.[37]
The need for frequent injections in DME represents a considerable burden for patients, especially with antiVEGF drugs. [38–40] In different studies, fewer IDI injections have been shown to be necessary to achieve similar visual and anatomical outcomes in DME patients [21, 41, 42], although the loss of vision mainly due to cataract must be controlled, which may be more common when IDIs are used. Further head-to-head trials will be needed to compare the efficacy of IDI and anti-VEGF therapy based on the patients’ clinical characteristics at baseline and their prior treatments, tailoring the treatment choice individually in a case-by-case basis. Towards this personalized medicine approach, several attempts have been recently reported to shed some light on predictive biomarkers for IDI response, based in retinal imaging (i.e. OCT) or aqueous samples.[43–46] Likewise, recent studies have been directed to identify those patients who don’t respond to anti-VEGF treatment,[47] as well as to determine the synergistic and beneficial effect of IDIs in combination with other treatments.[48, 49]
Significantly fewer IDIs were administered to treatment-naïve eyes than to previously treated eyes and indeed, many more treatment-naïve eyes received just 1 injection than previously treated eyes. However, when additional implants were required, the time to reinjection did not differ significantly between the two groups. This is an important point, as suggest that reinjections were timely performed in both groups when required. Such differences have not always been detected when this parameter has been compared between naïve and non-naïve eyes.[24, 50] Our results raise the interesting hypothesis that early treatment may reduce the treatment burden associated to IDI therapy in naïve DME, beyond the benefit already reported for refractory DME eyes when used as second line therapy. It is well recognized that managing DME with IDIs is generally associated with a need for fewer injections than anti-VEGF therapies, as well as longer periods between the need for treatment. The benefits to be gained from this need for fewer injections have already been recognised in the EURETINA guidelines for DME, whereby IDI use is recommended as a first-line therapy only in specific subgroups of patients. If confirmed in future studies, this finding may offer an additional reason to support the use of IDI as first-line therapy in a wider spectrum of DME eyes.
As found elsewhere, IDI therapy was well tolerated by DME patients. The main adverse event was high IOP but that could typically be managed with medication. Indeed, while nearly a third of patients developed a high IOP, it was controlled with topical antihypertensive drugs. There is no evidence of a previously cumulative effect of multiple injections on increased IOP, irrespective of pre-existing glaucoma or ocular hypertension (OHT).[51, 52] However, the probability of taking IOP-lowering medication increased considerably from 12 months to 24 months, an important consideration when using the IDI in routine clinical care.[53]
Our study has some limitations, such as the retrospective design of the study. In addition, a detailed comparison of the data obtained with that from previous clinical trials and other retrospective studies is complicated by the fact that they involve cohorts with different characteristics at baseline (Table 4). This is particularly the case of DME severity and the inclusion/exclusion criteria, and notably in terms of the baseline VA that differs substantially between trials, as well as the type and length of the prior treatments, and the intervals between the repeated IDI injections. Despite the absence of detailed comparisons, the results of the present study in a clinical setting are somehow comparable to the data from clinical trials. Furthermore, as the data is obtained from a cohort of patients not included in a clinical trial it better reflects patients seen in clinical practice, both treatment-naive and previously treated patients with DME. Therefore, similar outcomes can be expected of IDI treatment at other clinical centres for DME patients, as reported by previous smaller cohorts. Moreover, it is likely that the patients included in this study are patients that might otherwise not be recommended for such therapy as they do not conform to the criteria employed in clinical trials. It should also be noted that some of the patients considered to be naïve to treatment in this study had received prior laser therapy but not any prior intravitreal therapy. This may contribute to explain differences in treatment response and disease progression (and/or adverse events) between this cohort of naïve patients and those studied elsewhere.
Table 4
Comparison of dexamethasone intravitreal implant clinical trials and real-life studies of in diabetic macular edema (series ≥ 30 eyes)
| Study | Indication | Duration (months) | N | Baseline VA (letters) | Baseline CRT (µm) | Baseline %laser | Baseline %anti-VEGF | Baseline %IVTA | Final VA, (letters) | Final CRT (µm) |
| MEAD Boyer DS et al, 2014 | DME | 36 | 351 | 56.1 | 463.0 | 65.8% | 7.1% | 16.5% | 58.6 | 351.4 |
| MEAD-Treated Augustin AJ et al, 2015 | DME-Treated | 36 | 247 | 55.2 | 478 | 93.5% | 25% | 23.5% | 58.4 | 352 |
| CHAMPLAIN Boyer DS et al, 2011 | DME-PPV | 6 | 55 | 54.5 | 403.4 | 69.6% | 48.2% | 57.1% | 57.5 | 364.5 |
| BEVORDEX Gillies MC et al, 2015 | DME | 24 | 88 | 55.5 | 474.3 | - | - | - | 62.4 | 287.3 (*) |
| Escobar-Barranco et al, 2015 | DME-Naive | 6 | 40 | 59.6 | 568 | 0% | - | - | 71.1 | 323 |
| DME-Treated | 6 | 36 | 51.3 | 600 | 100% | - | - | 59.0 | 281 |
| Dutra et al., 2013 | DME-Treated | 6 | 58 | 52* | 543.24 | 74.1% | 75.9% | 67.2% | 58.5* | 420.16 |
| Totan et al., 2016 | DME-Treated | 6 | 30 | 57* | 517 | 56.7% | 100% | - | 64* | 411 |
| Bansal et al., 2015 | DME | 14.53 | 52 | 44* | 514.2 | 100% | 67.2% | - | 51* | 419.9 (6 months) |
| Bonnin et al., 2015 | DME | 4 | 39 | 51.5* | 559 | 44% | 49% | 36% | 81.5* | 477 |
| Guigou et al., 2015 | DME treated and naive | 6 | 78 | 53.9 | 537.6 | 42.3% | 52.6% | 17.9% | 60.1 | 384.6 |
| CHROME Lam et al., 2015 | DME (subgroup analysis) | 36 | 34 | 55* | 450.4 | 55.9% | 55.9 | 38.2 | 53 (6 months) | 259.5 |
| RELDEX Malclès et al., 2017 | DME naive and treated | 36 | 128 | 50.5 | 450 | 16.4% | 70.3% | 15.6% | 60.6 | 280 |
| IRGREL-DEX Iglicki et al., 2019 | DME naive and treated | 24 | 130 | 55* | 575 | 15% | 7.4% | - | 65.5* | 294.4** |
| This study: Zarranz-Ventura et al. 2020 | DME-All | 24 | 203 | 39 | 498.7 | 75.8% | 53.6% | 25.6% | 45 | 402.6 |
| Naive | 24 | 67 | 42.5 | 482.1 | 56.7% | 0% | 0% | 47 | 340.5 |
| Previously treated | 24 | 136 | 37.5 | 506.5 | 85.2% | 80.1% | 38.2% | 44 | 427.4 |
| DME: diabetic macular edema. VA: visual acuity. CRT: central retinal thickness. VEGF: vascular endothelial growth factor. IVTA: intravitreal triamcinolone acetonide. *Logarithm of the minimum angle of resolution values converted into ETDRS letters.** Calculated from publication data. |