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Effect of Prior Intensive Therapy in Type 1 Diabetes on 10-year Progression of Retinopathy in the DCCT/EDIC

The aim of this study was to examine differences between adolescents and adults in persistence of the benefits of intensive therapy 10 years after completion of the Diabetes Control and Complications Trial (DCCT)….

During the Epidemiology of Diabetes Interventions and Complications (EDIC) study, progression of retinopathy from DCCT closeout to EDIC year 10 was evaluated in 1,055 adults and 156 adolescents.

The results showed that during 10 years of follow-up, HbA1c (A1c) was similar between original intensive (INT) and conventional (CON) groups and between former adolescents and adults. At EDIC year 10, adults in the former INT group continued to show slower progression of diabetic retinopathy than those in the CON group (adjusted hazard reduction 56%, P < 0.0001), whereas in adolescents this beneficial effect had disappeared (32%, P = 0.13). Seventy-nine percent of observed differences in the prolonged treatment effect between adults and adolescents at year 10 were explained by differences in mean A1c during DCCT between adolescents and adults (8.9 vs. 8.1%), particularly between INT adolescents and adults (8.1 vs. 7.2%).

The Diabetes Control and Complications Trial (DCCT) clearly demonstrated the benefits of intensive diabetes therapy aimed at lowering blood glucose and HbA1c (A1c) as near to the normal range as safely possible. A marked reduction in retinopathy onset, retinopathy progression, and microalbuminuria was demonstrated in both the adult (18-39 years old at enrollment) and adolescent (13-17) cohorts treated with intensive therapy for a mean of 6.5 years. The Epidemiology of Diabetes Interventions and Complications (EDIC) study, the observational follow-up of the DCCT cohort, demonstrated that the differences in complication occurrence and progression between former intensive (INT) and conventional (CON) treatment groups continued in adolescent and adult cohorts during the first 4 years of EDIC despite similar A1c in the treatment groups during this time period. This phenomenon has been termed “metabolic memory.”

The EDIC study demonstrated the surprising and unexpected phenomenon that the benefits of improving glycemic control on the development and progression of retinopathy persisted for 4 years after completion of the DCCT, despite A1c levels that were similar in the two former treatment groups (metabolic memory). The benefits of INT therapy and improved glycemic control were substantial and similar in both adults and adolescents during and for up to 4 years after the end of DCCT, although adolescents had higher A1c as well as higher rates of hypoglycemia during DCCT.

In contrast, after 10 years of EDIC follow-up, the different metabolic memory effect between adults and adolescents presented here indicates that lower A1c during INT intervention is an important determinant of the long-term durability of its benefits. Indeed, the difference in DCCT mean A1c between adults and adolescents (8.1 vs. 8.9%) explains 79% of the observed difference in the metabolic memory effect on further retinopathy progression between adults and adolescents after 10 years of EDIC follow-up. Examining the A1c information further, adolescents started with a higher mean A1c level than adults at DCCT enrollment in both the INT (9.6 vs. 9.0%) and CON (9.5 vs. 8.9%) groups, and A1c remained higher in both groups during the entire DCCT period (8.1 vs. 7.2% in INT; 9.7 vs. 8.9% in CON). It was only during the EDIC follow-up that the mean A1c between adolescents and adults, as well as between former INT and CON groups, converged.

One possible explanation for the metabolic memory phenomenon is the slow accumulation, and subsequent slow degradation, of advanced glycation end products (AGEs). Indeed, DCCT patients in the INT group had lower concentrations of these AGEs in skin collagen than did patients in the CON group. The levels of these skin collagen AGEs were also shown to be associated with the subsequent increase in progression of retinopathy (and nephropathy) over the first 10 years of EDIC

From the results it was concluded that, prior glycemic control during DCCT is vital for the persistence of the beneficial effects of INT therapy 10 years later. Lowering A1c to as close to normal as safely possible without severe hypoglycemia and starting as early as possible should be attempted for all subjects with Type 1 diabetes. These results underscore the importance of maintaining A1c at target values for as long as possible because the benefits of former INT treatment wane over time if A1c levels rise.

Diabetes May 2010 vol. 59 no. 5 1244-1253