Prolonged effect of intensive therapy on the risk of retinopathy complications in patients with type 1 diabetes mellitus: 10 years after the Diabetes Control and Complications Trial

Abstract

Objective: To examine the persistence of the original treatment effects 10 years after the Diabetes Control and Complications Trial (DCCT) in the follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) study. In the DCCT, intensive therapy aimed at near-normal glycemia reduced the risk of microvascular complications of type 1 diabetes mellitus compared with conventional therapy.

Methods: Retinopathy was evaluated by fundus photography in 1211 subjects at EDIC year 10. Further 3-step progression on the Early Treatment Diabetic Retinopathy Study scale from DCCT closeout was the primary outcome.

Results: After 10 years of EDIC follow-up, there was no significant difference in mean glycated hemoglobin levels (8.07% vs 7.98%) between the original treatment groups. Nevertheless, compared with the former conventional treatment group, the former intensive group had significantly lower incidences from DCCT close of further retinopathy progression and proliferative retinopathy or worse (hazard reductions, 53%-56%; P < .001). The risk (hazard) reductions at 10 years of EDIC were attenuated compared with the 70% to 71% over the first 4 years of EDIC (P < .001). The persistent beneficial effects of former intensive therapy were largely explained by the difference in glycated hemoglobin levels during DCCT.

Conclusion: The persistent difference in diabetic retinopathy between former intensive and conventional therapy ("metabolic memory") continues for at least 10 years but may be waning.

Trial registration: (clinicaltrials.gov) Identifiers: NCT00360815 and NCT00360893.

Figure 1

Distribution of glycated hemoglobin (HbA_1c) values by Diabetes Control and Complications Trial (DCCT) treatment group at the end of the DCCT and at each of the first 10 years of the Epidemiology of Diabetes Interventions and Complications (EDIC) study among 1211 subjects evaluated for retinopathy at year 10 of the EDIC study. The box presents the quartiles of the distribution, the vertical lines show the 95th and fifth percentiles, the horizontal line is the median, and the mean is shown as +.

Figure 2

Estimated cumulative incidence of further 3-step progression of retinopathy from Diabetes Control and Complications Trial (DCCT) closeout to Epidemiology of Diabetes Interventions and Complications (EDIC) study year 10 (n=1349) (A) and from DCCT closeout to EDIC year 4 (n=1320) and from EDIC year 4 to EDIC year 10 (n=1105) (B) based on Weibull regression models adjusted for the level of retinopathy at the end of the DCCT, primary vs secondary cohort, glycated hemoglobin value on entry to the DCCT, and diabetes mellitus duration at DCCT baseline. Retinopathy was evaluated in 369 patients during EDIC year 1, 448 in year 2, 430 in year 3, 1225 in year 4 (1997), 338 in year 5, 440 in year 6, 406 in year 7, 204 in year 8, 233 in year 9, and 1211 in year 10 (2003). Subjects with prior scatter photocoagulation during the DCCT were excluded from analyses (26 in the conventional therapy group and 10 in the intensive therapy group). Patients who had further 3-step progression from DCCT closeout as of EDIC year 4 (n=212) and patients who were censored during the interval (n=32) were excluded from the analysis of incidence over years 4 to 10. CI indicates confidence interval.

Figure 3

Estimated cumulative incidence of proliferative diabetic retinopathy (PDR) or worse from Diabetes Control and Complications Trial (DCCT) closeout to Epidemiology of Diabetes Interventions and Complications (EDIC) year 10 (n=1314) (A) and from DCCT closeout to EDIC year 4 (n=1285) and from EDIC year 4 to EDIC year 10 (n=1215) (B) based on Weibull regression models adjusted for the level of retinopathy at the end of the DCCT, primary vs secondary cohort, glycated hemoglobin value on entry to the DCCT, and diabetes mellitus duration at DCCT baseline. The sample size is based on all EDIC evaluations in all subjects, including those at EDIC years 4 and 10, and those in a quarter of these subjects at other EDIC years. Patients with prior PDR or worse during the DCCT were excluded from all the analyses (52 in the conventional therapy group and 26 in the intensive therapy group). Patients who had PDR during the first 4 years of EDIC follow-up (n=63) and patients who were censored during the interval (n=36) were excluded from the analysis of incidence over years 4 to 10. CI indicates confidence interval.