American Diabetes Association
MM_Supp_05.2021_final.pdf (419.86 kB)

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)

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posted on 2021-09-21, 17:59 authored by John M. Lachin, David M. Nathan, the DCCT/EDIC Research Group
The Diabetes Control and Complications Trial (DCCT, 1983-1993) showed that intensive therapy (mean HbA1c 7.2%) compared with conventional therapy (mean HbA1c 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 HbA1c levels. The DCCT cohort has been followed in the Epidemiology of Diabetes Interventions and Complications study (EDIC, 1994 to date).

Early in EDIC, mean HbA1c 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 HbA1c 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.


The DCCT/EDIC has been supported by cooperative agreement grants (1982–1993,2012–2017, and 2017–2022) and contracts(1982–2012) with the Division of Diabetes, Endocrinology, and Metabolic Diseases of the National Institute of Diabetes and Digestive and Kidney Diseases (grants U01 DK094176 andU01 DK094157) and through support by the National Eye Institute, the National Institute of Neurological Disorders and Stroke, the General Clinical Research Center Program (1993–2007),and Clinical and Translational Science Center Program (2006–present) (Bethesda, MD). Industry contributors have had no role in the DCCT/EDIC study but have provided free or discounted supplies or equipment to support participants’ adherence to the study: Abbott Diabetes Care (Alameda, CA), Animas Corporation (West Chester, PA), Bayer Diabetes Care(Tarrytown, NY), Becton Dickinson (Franklin Lakes, NJ), Eli Lilly and Company (Indianapolis, IN), Extend Nutrition (St. Louis, MO), Insulet Corporation (Bedford, MA), LifeScan, Inc. (Mil-pitas, CA), Medtronic Diabetes (Minneapolis, MN), Nipro Home Diagnostics, Inc. (Fort Lauderdale, FL), Nova Diabetes Care (Billerica, MA), Omron (Shelton, CT), Perrigo Diabetes Care (Allegan, MI), Roche Diabetes Care (Indianapolis, IN), and Sanofi U.S. (Bridgewater, NJ).


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