Understanding Metabolic Memory: The Prolonged Influence of Glycemia During the Diabetes Control and Complications Trial (DCCT) on Future Risks of Complications During the Study of the Epidemiology of Diabetes Interventions and Complications (EDIC)

Abstract

The Diabetes Control and Complications Trial (DCCT, 1983-1993) showed that intensive therapy (mean HbA_1c 7.2%) compared with conventional therapy (mean HbA_1c 9.0%) markedly reduced the risks of retinopathy, nephropathy, and neuropathy, and these reductions in complications were entirely attributable, statistically, to the difference in mean HbA_1c levels. The DCCT cohort has been followed in the Epidemiology of Diabetes Interventions and Complications (EDIC) study (1994 to date). Early in EDIC, mean HbA_1c levels in the former intensively and conventionally treated groups converged. Nevertheless, the beneficial effects of DCCT intensive versus conventional therapy on microvascular complications not only persisted but increased during EDIC. The differences in complications during EDIC were wholly explained, statistically, by differences between groups in HbA_1c levels during DCCT. These observations give rise to the concept of metabolic memory. Subsequent similar findings from the UKPDS gave rise to a similar concept, which they called the legacy effect. In this report, we present the evidence to support metabolic memory as both a biological and epidemiological phenomenon and discuss potential underlying mechanisms. We also compare metabolic memory and the legacy effect and conclude that the two are likely biologically similar, with comparable effects on long-term outcomes. The long-term influence of metabolic memory on the risk of micro- and macrovascular complications supports the implementation of intensive therapy, with the goal of maintaining near-normal levels of glycemia, as early and as long as safely possible in order to limit the risk of complications.

Figure 1

The mean ± SE HbA_1c over the average of 6.5 years of follow-up in the DCCT (9.5 years maximum) and up to 26 years of follow-up in EDIC for subjects in the DCCT originally assigned to intensive and conventional treatment groups. Adapted with permission from the American Diabetes Association (25).

Figure 2

Cumulative incidence of further progression of retinopathy by at least 3 steps from the level at the end of the DCCT during the subsequent 8 years of follow-up during EDIC. Subjects experiencing laser therapy during the DCCT were excluded from analysis. Cumulative incidence of new albuminuria (AER >300 mg/24 h) during 8 years of follow-up during EDIC. Subjects developing albuminuria during the DCCT were excluded from analysis. Reprinted with permission from the Journal of the American Medical Association (9).

Figure 3

The smoothed estimate of the day-to-day incidence (hazard) rate of sustained 3+ step progression of retinopathy within the former intensive vs. conventional treatment groups over 26 years of EDIC follow-up (left), which represents biological metabolic memory, and the cumulative incidence of 3+ step progression (right), representing epidemiological metabolic memory or the legacy effect. The cumulative incidence functions were computed using the Turnbull estimate for interval-censored data, smoothed using natural cubic splines, and differentiated to yield the smooth hazards estimate.