The duration of diabetes, poor glycemic control, high blood pressure and proteinuria are known risk factors when observing the development of diabetes related complications (11). Globally, DR has been one of the leading causes of blindness among the working age population and the most common complication of T1D (12). However, the number of visual impairment due to DR has decreased during the past decades (7, 13). More effective screening for DR and improvement in the management of both diabetes and DR have been key factors in the reduction of visual impairment (7). Accordingly, DME related visual impairment was rare and reduced in the present study during the 15-year follow-up in a population-based cohort of T1D patients with DME. We might assume that the improvements in both diagnostic accuracy and treatment possibilities of DME during the past 15 years have played an important role in this phenomenon.
Warwick et al. has reported that DME is associated with the duration of diabetes (3). In agreement with this, our results showed that in T1D patients DME developed almost 10 years later than the first signs of DR. One may speculate that the prevalence of DME increases along the severity of DR. However, only less than one fourth of the study patients with DME had PDR. Previous study has revealed a high 94% prevalence of any DR and 35% prevalence of PDR in patients with T1D since childhood and duration of T1D for over twenty years (14). The T1D patients with DME in the present study differ from this cohort of patients with T1D since childhood, according to older age at the onset of diabetes and the lower prevalence of PDR.
The treatment for DME has revolutionized during the last 15 years after the introduction of intravitreal anti-VEGF agents (7, 15). Laser photocoagulation has been the standard treatment for DME for almost three decades, but currently anti-VEGF agents are considered the first line treatment alternative in center-involving DME (8). Several large clinical trials have demonstrated that the improvement of BCVA > 15 ETDRS letters has been achieved by anti-VEGF agents in 33–45% of patients with either type 1 or type 2 diabetes (8, 16),(17). Superior visual outcomes have been reported by ranibizumab treatment compared to treatment performed by laser, and a higher proportion of patients has gained significant > 10–15 ETDRS letter increase in BCVA when treated with anti-VEGF (6). Similarly, the BOLT study has revealed that the number of DME patients gaining > 15 ETDRS letters was significantly greater when treated with bevacizumab compared to macular laser (18, 19). In agreement with these results, DME patients gaining the most ETDRS letters in the current real-world study were treated by bevacizumab and the best long-term visual outcomes were achieved with combination treatment with both anti-VEGF and macular laser. However, previous studies have suggested that DME patients with relatively good BCVA could be observed when BCVA remains stable (20–22). Our real-world results show, however, a decrease in BCVA in the observation group of patients receiving no treatment in the long term, suggesting that the early treatment of DME might be reasonable to maintain good vision. This is of particular importance when considering the necessity of functional vision for these working-aged, relatively young patients with T1D. Accordingly, the benefits of early intensive treatment by anti-VEGF has recently been shown to result in satisfying long-term visual outcomes (23). Even in the cases of no BCVA improvement, anti-VEGF treatment may improve contrast sensitivity in DME patients (20), and thus provide the best long-time safety in maintaining good visual function.
Beyond VEGF, the presence of inflammation is known to affect DME pathogenesis and intravitreal corticosteroids may be used to treat DME (8). In our T1D patient cohort none of the patients received intravitreal corticosteroids. This might be explained by the known side-effects of corticosteroids, such as cataract development or possible increase in intraocular pressure (24). Most study patients, at the average age of 47 years, might be assumed not to have sight-threatening cataract, and the formation of cataract might thus be attempted to avoid by using primarily anti-VEGF drugs classified with a positive safety profile.
There are some limitations in our study. First, the retrospective nature of the study might affect the assembly of different treatment groups and thus comparison of the outcomes. Understandably, baseline visual acuities varied according to the presence or lack of central-involving edema in the participants, although there were no defined BCVA-level for the choice of each treatment. Taking this into consideration, the intra- but no intergroup analysis in the long-term changes in BCVA were completed. Secondly, the underlying risk factors for DME were only partly available, and precise data of the blood glucose levels, cholesterol and kidney function were lacking. Thirdly, the current data did not include any patients treated with intravitreal corticosteroids and the visual outcomes of that treatment cannot be concluded. We consider the inclusion of only T1D patients with DME as part of the current study as a strength in contrast to most studies that are completed with patients with both type 1 and type 2 diabetes. There are significant differences in the pathogenesis as well as risk factors for DME between these patient groups and combining them might be a possible source of bias. Also, the real-world setting and long-term follow-up of the population-based cohort might be considered as strengths of the present study.
In conclusion, our results suggest that early intervention of DME by intravitreal anti-VEGF treatment alone or in combination with laser might be beneficial in terms of visual improvement in patients with T1D. Visual acuity slightly decreased or remained stable in those observed or treated with laser, respectively. A low rate of DME recurrences and the beneficial effect on contrast sensitivity (20, 24) highlight the importance of timely anti-VEGF in maintaining good visual function in patients with DME.