DCCT, EDIC, and “Metabolic Memory”

 Dr. Schneider and Dr. Leahy discuss the surprising result of "metabolic memory" from the findings of the DCCT and EDIC trials.


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. [W]hat I’d like to turn to is the next phase after the DCCT trial formally ended. There was a wonderful natural observation study called the EDIC study So 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:  [S]o what the EDIC trial 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…And they were 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 a 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 understand 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, 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 macrovascular complications 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. As we finish up here I can’t help but just have you comment, if you would, around the type 2 diabetic patient. Do any of the things that we just described really bear out in type 2 diabetes?
JL: So, it turns out we asked does it work in type 2 and then five years later in 1998 was the publication of the famous UKPDS, the United Kingdom Prospective Diabetes Study that was not actually perfectly analogous to the DCCT—it was a little bit of a different trial—but it was looking at first drug therapy in type 2 diabetes in people who were very early in the course of the disease, looking at an attained hemoglobin A1C with intensive therapy of 7 versus about 8 in people with conventional therapy. So not quite the same delta that we had in type 2, but with very similar results, which showed a relationship between intensive blood glucose control and prevention against microvascular complications in type 2 diabetes. No clear prevention of macrovascular, although that’s a very, very complicated subject. How one group took metformin and maybe metformin showed some cardiovascular protection—that’s open to a bit of debate—and there was a reduction in myocardial infarction in this trial in absolute terms, but not statistical terms.
So again, we were sort of left with well, intensive blood glucose control seems to be good also in type 2 for microvascular. And then the UKPDS did exactly what the DCCT did, which is to basically wait about another eight to nine years. Again, the trial was finished. People were, you know, let out of it. Their A1Cs normalized in the intensive group versus the control groups. Everything else normalized including blood pressure, and then they were actually studied eight or nine years later with the same finding, which was continued, now proven, protection against cardiovascular disease in the people who had had the A1Cs that were intensively controlled versus those who hadn’t. Same molecular mimicry.
And actually one of the things that gets lost in this conversation is if you read the original UKPDS what you took away from that is that blood pressure was a better control target than A1C because blood pressure during the trial did actually seem to confer some cardiovascular benefits while blood glucose control didn’t really. But at the end of the continuation phase, that eight years later, when A1C had normalized, blood pressure had normalized, the cardiovascular protection lingered despite A1Cs coming together, but the blood pressure related one didn’t. So if there is a benefit of intensive blood pressure control in diabetes you need to keep it controlled. There isn’t this sort of long-term memory.
And then as a final closing of the loop there’s actually another trial we talk a lot about—something called the Steno-2 trial, which is a small trial of taking people in Scandinavia and trying to intensively control not just their blood glucose, but blood pressure and lipids, and at the end of that trial there was pretty good cardiovascular protection, but then everything was stopped. They were studied an average of seven or eight years later, and they still had this lingering cardiovascular benefit. So this whole idea of mimicry, or at least this sort of molecular protection, has been shown not just in type 1 diabetes, but type 2 diabetes. It seems to be a biological fact.
DS: Well, Jack, I really want to thank you for that review. 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.