EDIC and Metabolic Memory   (June 26, 2013)

The results of the DCCT (Diabetes Control and Complications Trial) were announced twenty years ago, on June 13, 1993, in a two-hour session at the Annual Meeting of the American Diabetes Association, and were published soon after: The Effect of Intensive Treatment of Diabetes on the Development and Progression of Long-Term Complications in Insulin-Dependent Diabetes Mellitus . This major scientific study was designed to answer the question whether "tight control" of blood sugar levels will prevent diabetes complications in people with T1DM. And the simple answer is — “yes.”

This summer, results from 18 years of followup on the DCCT volunteers were announced at the Annual Meeting of the American Diabetes Association. The results are simply spectacular, and continue to show decreased risk of diabetes complications in patients who were placed on tight glycemic control soon after diagnosis.

The original DCCT study included 1441 teenagers and young adults with type 1 diabetes, who were randomly assigned to either “conventional care” (which was standard care at the time the study was designed: either urine or blood sugar tests, one or two insulin injections daily, and "routine" three month follow-up visits), or to “intensive treatment,” which included initial hospitalization for education and stabilization, four or more blood sugar tests daily, use of either an insulin pump or multiple daily insulin injections, monthly office visits, and frequent (sometimes as often as daily) telephone calls between the patients and the DCCT's diabetes nurse educators.

Patients were enrolled over several years, with the range of participation of about three to nine years. During the ten years of the study, there was only an extremely low dropout rate of only 1%.

The results of the DCCT study had shown an overwhelming difference in the chances of developing three major diabetic microvascular complications: there was a sixty-two percent reduction in relative risk of diabetic retinopathy (eye disease), fifty-six percent less progression of kidney disease, and sixty percent less progression of neuropathy (nerve damage), in the intensively-treated group of patients compared to conventional care. All these decreases in risk were seen in all subgroups, male/female, teenage/young adult, and recent/remote onset of diabetes. The differences between the intensive and conventional groups were apparent within three years, and the curves showing the rate of developing complications of the two groups progressively diverged as the years went by. There was no increase for the intensive group in deaths, behavioral changes, or other adverse outcomes, with the exception of the increased frequency of hypoglycemia, and somewhat greater increase in weight gain in patients in the intensive group.

At the time that the DCCT was wrapping up in 1993, the investigators realized that it would be helpful to continue to follow these patients after the study’s conclusion. Hence, a followup study was designed; it was named the Epidemiology of Diabetes Interventions and Complications (EDIC) trial.

In EDIC, the subjects who had participated in the DCCT were all invited to participate in long-term followup, and those subjects who had been on conventional therapy were allowed to switch to intensive therapy (and most did). The subjects have been followed annually, with their diabetes care now provided by their own health professionals (rather than by the DCCT investigators). Almost all of the DCCT subjects chose to enter the EDIC trial, and they have continued to be followed for what is now an additional 18 years (from 1994 till now).

During the 18 years of EDIC, the average A1C of the participants has settled in at about 8%, whether they had been on intensive or conventional therapy during the DCCT itself. In other words, blood glucose levels in the intensive treatment group rose, and those of the conventional group declined, so that blood glucose levels have become nearly the same between the two treatment groups. (During the DCCT, the intensive therapy group had an average A1C about 7% and the conventional group about  9%.)

And during the additional 18 years of followup, the good outcomes seen in the DCCT continued:  quoting one of the study’s co-chairs, "As we follow this population longer, we've been able to show that early benefits with regard to early complications has extended… We've demonstrated that loss of kidney function is reduced, people develop less severe eye complications, and we see a host of other benefits on long-term severe complications that we didn't see during the initial trial because the patients were too young and had diabetes for a relatively short period of time."

One of the most surprising findings of EDIC is a phenomenon that the researchers are calling “metabolic memory.” It’s hard to understand without looking at a graph, so I’m reproducing one here from an EDIC publication at the NIH website:

Remember I mentioned that during EDIC the BG and A1C control of the conventional group matched that of the intensive group? That’s demonstrated on the lower half of this graphic, showing 10 years of data from EDIC. The big surprise is in the top half of this graphic, which shows that despite the similarity of BG control during EDIC, the intensive group from the DCCT has continued to outpace the conventional group from the DCCT in reducing the risk of complications. In this graphic, it’s retinopathy risk reduction that’s displayed. During the presentation last week at ADA, similar diverging lines were shown repeatedly for other diabetes complications.

This unexpected phenomenon -- that early aggressive therapy makes a difference in outcomes many years later, when compared to lackadaisical early therapy -- is what’s being called “metabolic memory.” (The phenomenon has also been seen in a big somewhat similar study in T2DM, the UKPDS, where it has been called a "legacy effect" by the UKPDS investigators.)

So, what’s the upshot of collecting tons of data on over a thousand young adults with T1DM? I think the most important outcome is the finding of the “metabolic memory” effect: getting started on a tight-control diabetes program pays off in decreased risk of complications, and getting started early pays off even better.

Or, as has been said many times in different words, “control matters.”