History of The Diabetes Control and Complications Trial (DCCT)
Dr. Doron Schneider and Dr. Jack Leahy discuss The Diabetes and Complications Trial, a landmark study that still influences the standard of diabetes patient care.
Dr. Doron Schneider (DS): Hi, I’m Dr. Doron Schneider. I’m a general internist at Abington Health right outside of Philadelphia, and today we’re going to talk about a landmark trial called the DCCT trial, and here to discuss this landmark trial with me is Dr. Jack Leahy.
Dr. Jack Leahy (JL): Hi Doron. I’m Jack Leahy, and just to introduce myself I’m the head of endocrine here at the University of Vermont in Burlington, Vermont.
DS: Fabulous. Well, thank you for spending a few minutes with us here today, Dr. Leahy. We wanted to really reflect on the history of the DCCT given that we’re coming up on really 30 years of achievement that reflects both the DCCT and the continuation study called the EDIC study. So, just to give everyone a foundation, can you tell us a little bit about really what was the construct of the DCCT? Can you give us a little bit about who were the patients, what were the questions they were trying to answer back 30 years ago when the trial had just launched?
JL: Yeah, I actually love that you said it’s a landmark trial. I think from my perspective and probably the diabetes perspective in general it’s really a stunning clinical trial that has clearly stood the test of time and many people still view [it] as one of the great clinical trials in our field.
So this is a trial that was designed to deal with a really controversial question many years ago—a question that actually younger people have really sort of forgotten, which was: Is there actually a proven benefit of intensive blood glucose control in patients who have diabetes, and if there is what actually is that benefit? And the question back then was more focused on microvascular complications as opposed to macrovascular complications because really the classic diabetes complications back in the ‘80s and ‘90s related to issues in terms of the eyes and kidneys and legs and that kind of thing.
This was a trial of taking patients with type 1 diabetes broken into two subgroups. So about half of the patients—and this is a US trial and on average, I think, there were 1440 patients or so that were enrolled—about half of them were absolutely free of any microvascular complications and in particular [from any] retinal microvascular complications. And the other half had had their illness for a little more on average than five years, and they had some very, very modest retinal complications—nothing terribly overt. So the design of the trial was to intensify blood glucose control in a subgroup and then look at the outcomes, primarily in terms of retinal health, but also many of the other complications in terms of peripheral vascular issues, neuropathy, and also in terms of kidneys, and then compare that safety in terms of rates of hypoglycemia and really anything else that might have been identified.
Now, what’s really crucial in sort of thinking about this trial is it was published in the New England Journal in 1993 and it was performed over an average of six to seven years. So you go back six or seven years and it really was performed from the end of the ‘80s through the beginning of the ‘90s and thus was designed in protocol even before that. So this is a time preceding so much of the standard technology in therapeutic things that we use today. So, intensive therapy back then was really defined as, “Well, you can’t use NPH insulin” [neutral protamine Hagedorn insulin, an intermediate-acting form of insulin]. It was kind of known that NPH was a difficult insulin. So intensive therapy in the mid-1980s was either putting people on an insulin pump and that was about a little more than half the patients or giving them a basal bolus insulin program. But [at] that time the current analog insulins we have didn’t exist, so [the] basal bolus insulin program was mostly using Ultralente insulin [a long-acting form of insulin] and then regular insulin at meals (multi-shot insulin program with some blood glucose testing), as opposed to conventional control, which back then was really NPH and regular [insulin] with virtually no blood glucose testing. And then, again, they [the patients] were followed for an average of about seven years to see what happened.
The general sort of results were that in the intensive group they were able actually to get an average hemoglobin A1C over all of those years of about 7, which is actually stunning if you kind of think about it, as opposed to the conventional group, which were on average of about 9, so they had a 2 percentage point difference. And they just saw huge reductions in microvascular complications—stunning reductions in both retinal problems and in early kidney problems and in peripheral neuropathy of more than 50 plus percent for all of those over the six to seven years of the trial. Th[is was] the beginning of the whole concept that has now driven diabetes care since that time, [in] which intensive blood glucose control has a major if not dominant impact on risk of microvascular complications .
DS: Well, what a wonderful intro to the trial—its design, the primary endpoints and then some of the secondary looks at harm. If you can just tell us a little bit about the patients who were enrolled in the sense of their duration of diabetes. You referenced that they were relatively free of some complications, but can you tell us just so that we understand about how generalizable this trial is to the patients we see in the office. First, of all you did mention they were type 1, but how far into their disease were they? Were they young, were they middle aged, where they older? Can you just give us a frame of reference at a time of entry to the trial?
JL: Well, you know, generally fairly young into early adult years. I think on average children were not included, but adolescents were and then into early adult years. Again, half the group were free of any kind of known complications that had a duration of less than five years of the illness. The other half had very, very modest complications and, I think, were allowed to have a duration anywhere from 5 to 15 years is my memory. So, the kind of patients I think we would think about [are] pretty early in the course of type 1 diabetes and fairly young and, actually, that will be important as we start to think about the EDIC trial—but pretty early in the disease. This is in no way a trial of taking people with long-standing type 1 diabetes; established complications; high risk of cardiovascular disease, and then study[ing] the impact of intensive blood glucose control. That’s not this trial. This is when someone’s pretty early in the course of the disease and still very healthy related to this disease. [It’s looking at] how intensive therapy might have a benefit at that time.
DS: Excellent. That does help frame out the trial design. This trial, the DCCT, in the observation period set the standard as you just articulated, emulated by other trials and clearly in its thirtieth anniversary is still holding the test of time.
But what I’d like to do is wrap it up right now and refer our listeners to betacellsindiabetes.org for additional information. And at this point, again, one final thank you to Dr. Leahy for an eloquent review. We look forward to seeing you next time. Thank you, Dr. Leahy.
JL: Thank you very much.