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 and the continuation study called the EDIC study. So, just to give everyone a foundation about what the trial is and the EDIC study is, can you please tell us a little bit about what happened in the EDIC study, which is a continuation observational trial? How many years did it go for, and what happened to the two arms of the DCCT?
JL: Yeah, so this actually just I think a fabulous story. I am of the generation, I think you are too quite frankly, where when the DCCT was published I mean it was incredible news in 1993. It changed our world. It changed how we thought about things. But somehow we thought it was a complete story and that the story was if you intensively treat people with type 1 diabetes in a way that was doable, and increasingly doable as treatments got better, that you [would] have a real[ly] important protective effect against microvascular complications. But in the original trial there was no benefit for macrovascular complications and, in part, that was because these were pretty young, for the most part healthy, people who, you know, were not terribly at risk for cardiovascular events and so, you know, you’re not going to see much of a protective effect if not much was happening in the control group.
So that’s kind of what we thought was the finished story and so what the EDIC trial did was to take people who were now finishing the DCCT trial and continue to follow them, but no longer in any kind of controlled environment. So essentially the trial stops, and all of the intervention stops so that the people who were in the intensive group, you know, within about a year A1C started to loosen up a little bit and sort of drifted up to the high 7s because that’s what happens. It’s not easy to keep an A1C of 7 percent with type 1 diabetes. It’s really hard work and when you’re no longer in the clinical trial then it just loosened up a little bit. So it rose a bit. Then the people who were in the control group who previously had an A1C of 9 percent they started to hear all of the wonderful things attached to the better control and so they just naturally improved because, I think, the medical profession had adopted that, you know, this is important so their A1Cs came down to the high 7s. And so somewhat serendipitously these two groups within a year or so essentially equalized in terms of hemoglobin A1C and actually equalized in terms of sort of treatment approaches. So they became one and the same now. There was no obvious difference between the two.
And then they were just followed…for close to another ten years. Data w[ere] periodically collected to understand the different health issues of these individuals and see how they’re doing. So that’s the design with some pretty interesting surprises.
DS: Yeah, so very crisp review of that observational follow-up study which lasted almost 20 years and you eluded to the interesting findings. So, let’s start off first with the primary endpoints regarding microvascular complications. What did we see as it relates to them?
JL: So, I guess maybe to try and und erstand why these are interesting you might take one step back and say, “Well, what might you have predicted?” And I think probably people would say, “Well, the prediction would be then when you have this difference in A1C, this intensive therapy difference, is you’ll see a protective effect against something, i.e., microvascular complications as well as identified. But now, if the difference in A1C goes away then in theory the protective effect will go away. It may take a period of time, but the concept would be that it will go away. I mean you need ongoing intensive therapy to maintain the benefits. And that is not at all what was seen. The initial protection against microvascular complications, and the ones that have been mostly focused on are retinal, but there’s been also neuropathy and in some of these, they continue. Something about that early period of intensive therapy gives an ongoing effect that does not require maintenance of that intensive difference in A1C, which is kind of stunning if you think about it.
DS: Right, and I believe that that concept has been one that has been named metabolic memory. I believe that it has really fundamentally altered the way that we think about the early and aggressive treatment of patients who are just diagnosed really for all the above reasons that you’ve just articulated. This is a lasting impact over decades to really get that initial early control. The beta cells have memory.
So, let’s then focus on the big other shock that you’ve alluded to a couple of times regarding macrovascular complications. Now, you did clearly state that this is a very young population. They didn’t have a lot of co-morbidities. They didn’t have a lot of cardiac risk factors. So we didn’t see a lot of endpoints as it relates to cardiac outcomes in the DCCT. What did we see as it relates to cardiovascular outcomes in EDIC?
JL: So, I love how you framed the question because the shock— this is just more than shock. I mean this is just really an altering event in our world, which is this same lingering metabolic memory, or whatever you want to call it, was true for cardiovascular disease, and so all of a sudden because the trial now drifted out to another ten-plus years from the original seven years of the DCCT, you’re getting older people who are having higher cardiovascular event rates and the same protection—sizable protection; we’re not talking something little, dinky, I mean, we’re talking at the sort of 30 to 40 percent protective range—was still there years after the trial was over. And again I emphasize that not only had A1C come back to be equal during the ten years they weren’t in the trial, but blood pressures were the same, lipids were basically the same, I mean, none of the cardiovascular risk factors that we think about easily explains any of this. There was something magical—magical!—about that first six to seven years of intensive blood glucose control in these patients, which continued to be present 20 years later, and I don’t think we have a time where it’s ended yet. I mean, maybe it’s going to go forever. So [this was] a stunning observation that now covered not just microvascular complications, but and totally moved the conversation of intensive blood glucose control and protection…[to cover] not just…microvascular issues, but long-term macrovascular issues.
DS: So it really crossed the gamut of microvascular and macrovascular improvements in endpoints and thus was a trial that really shook the landscape and will never be repeated. I’m quite confident of that.
Jack, I really want to thank you for reviewing the EDIC study and really giving us the context as it relates to how [to] monitor patients over time, and to help us all be grounded in fact—and not fiction, but fact—as to what expectations we can get from that type of control. 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 of the trials. We look forward to seeing you next time. Thank you, Dr. Leahy.
JL: Thank you very much.