In this 20-year study of 1,604 adolescents with type 1 diabetes, the prevalence of retinopathy has continued to decrease in parallel with a decline in HbA1c
and intensification of management. In contrast, there has been a recent plateau in the prevalence of microalbuminuria and peripheral nerve abnormalities. Severe hypoglycemia has remained unchanged. Although this was not an interventional study, we have confirmed a contemporary association among intensive management, improved glycemic control, and lower risk of retinopathy, more than 20 years after the DCCT was performed (1
). Our findings provide some reassurance for lower glycemic targets and increased use of MDI and CSII in children and adolescents with type 1 diabetes.
The strengths of this study include the sample size, with 1,604 adolescents and 2,030 assessments over 20 years. This was a free-living observational trial, and patient characteristics (diabetes duration, demographics) were comparable over the four time periods. It is a well-described population, with comprehensive data collected at each visit. All patients were assessed at one center, and there were few changes in the complications assessment methods throughout the study period, with a small number of changes in assessment personnel and the same retinal specialist grading the retinal images.
There are several factors that may influence the interpretation of our findings. In our last report (7
), patients were matched according to age across time periods, whereas in the current study, there was a small increase in age across the four time periods (from 15.9 to 16.4 years). However, given the recognized association between retinopathy and age, this may be expected to bias the results toward a higher prevalence of retinopathy recently, rather than the reduction that we observed (2
). The inclusion of more than one visit for some patients, although in different time periods, may have introduced response bias. However, there was no difference in trends over time () when only one assessment per patient was analyzed. Multivariate analysis of factors associated with microalbuminuria was limited by the low prevalence of microalbuminuria, with only 65 cases over 20 years (4%). We therefore used a surrogate measure, borderline elevation of AER/ACR, which has many of the same risk associations as microalbuminuria (20
). Over the time course of the observation period the albumin assay methods changed in the 5th year of T2 and during T3. This is unlikely to have biased our results, since we have observed a plateau in AER elevation over this period with reduction only between T1 and T2.
Retinopathy was found in approximately half of adolescents with type 1 diabetes after a median duration of ~9 years in the early 1990s, compared with only 12% in recent years (). It is of interest that in subgroup analysis of patients treated only with intensive management in T4, there was some evidence for reduced risk for retinopathy in those treated with CSII compared with MDI. Given there was no difference in A1C between groups, we hypothesize that reduced glycemic variability may have contributed to this difference. Although others have found a similar trend in decreasing HbA1c
with time (21
), to the best of our knowledge there are no studies demonstrating a specific benefit of CSII over MDI on complications in adolescents. There are now more patients than ever reaching the recommended HbA1c
target of 7.5%. The prevalence of complications in these patients is lower than in those who did not reach the target range, supporting this as the target.
Other potential modulators of the reduction in retinopathy should be considered. Earlier diagnosis of diabetes in more recent years could result in better preservation of C-peptide reserve and hence potentially less glycemic variability. We were unable to assess this possibility because C-peptide was not available in the early time periods; however, there is no evidence for a reduction in diabetes ketoacidosis at presentation over the 20 years. Another potential cause for reduction in retinopathy could be concurrent use of other medications, but very few of the adolescents were taking antihypertensive or lipid modulators (<1%). It is possible that the health message of smoking has resulted in a lower rate of smoking, but we were unable to objectively measure this (13
). It remains most likely that the improvement is a result of the demonstrated glycemic control. This analysis could not inform us of whether the current glycemic target of 7.5% is optimal, since there were too few participants meeting a target of 7% to find a significant difference in complication rates at that threshold.
Although the prevalence of microalbuminuria has decreased previously, the prevalence of both borderline AER/ACR and microalbuminuria appears to have reached a plateau in the last three time periods. Although microalbuminuria remains uncommon in this age-group, it is of concern that almost one-third of adolescents had borderline elevation of AER/ACR, especially since we and others have shown previously this is risk factor for future development of microalbuminuria (22
). Borderline AER/ACR was associated with recognized risk factors including DBP, older age, higher HbA1c
, higher weight SDS, higher insulin doses per kilograms (both surrogate markers for insulin resistance), male sex, and management with 1 to 2 injections per day (6
). Notably, socioeconomic disadvantage was also significant in multivariate analysis. This may be a confounder for CSII/MDI use since in our population CSII is predominantly used by patients who have private health insurance, who are from higher socioeconomic groups (24
The initial increase in peripheral nerve abnormalities over time also reached a plateau in the two recent time periods. We have shown previously a positive association between height and peripheral nerve abnormalities. In the current analysis, when peripheral nerve function was adjusted for height, surprisingly only fewer injections actually reduced the risk of peripheral nerve abnormalities without the more usual variables increasing the risk (7
Both retinopathy and borderline AER/ACR were associated with an improvement in socioeconomic status over time. It is possible that there has been a bias toward higher socioeconomic status individuals who attended a complications assessment in recent years, in parallel with improved knowledge. The coding of socioeconomic status is postcode based and determined every 4 years by the Australian Bureau of Statistics; therefore the change in socioeconomic status may represent reclassification of the same area rather than a change in patient circumstances.
In conclusion, we have observed a marked decline in retinopathy in adolescents in the past 20 years in association with a decrease in HbA1c and intensification of treatment regimens. Other microvascular complications have plateaued, with microalbuminuria remaining uncommon. We found some evidence for a specific benefit of CSII; ongoing observation of patients treated in this technological era will demonstrate whether CSII and other tools (such as continuous glucose monitoring) have specific advantages over MDI.