DCCT and EDIC: Impact of Tight Control on Hypoglycemia

 Dr. Schneider and Dr. Leahy, discuss the findings of the DCCT and EDIC studies as they relate to the impact of tight control of diabetes in the early stages of the disease.


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.
JL: 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.
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: So, you clearly reference the outstanding benefit that we saw in microvascular disease in the order of 50, 60, almost 70 percent reduction. In that benefit we did see that it did come at some degree of cost. What did we learn about really driving down that blood sugar to a mean of 7? What happened to hypoglycemia?
JL: So the answer to that is they had a much higher frequency of hypoglycemia, and a particular serious hypoglycemia, but, I think, the proper answer to that must frame the timeframe of when all this occurred. So, as I already said the only insulins which were available were really the insulins which precede the analogs which we have today—so just by definition not as safe as what we think about with our current analogs. So not only is it a fold difference in terms of rate of hypoglycemia that I’ll mention in a second, but also the absolute numbers actually have importance as we think about how things have really evolved over the last 25 years since this trial.
So what was seen back then [was] a three-fold higher rate of serious hypoglycemia and admissions to the hospital for hypoglycemia versus the control group. And I think when I try and teach this trial to students and to the residents, I try and point out to them this is not junky hypoglycemia. You know, the definition of serious hypoglycemia is, traditionally then—and has continued since then—as requiring help from someone else. But if you really talk to patients these are events that they don’t forget or that their spouses or other people who’ve been involved don’t forget. These are seizures. These are unconsciousness. These are car accidents. I mean these are major events. And back then, a three-fold higher rate, I mean, that is very, very serious in terms of that observation….It was clear intensive therapy back then came with a significant price in terms of hypoglycemia.
The other issue that I think is interesting is that when you look at the absolute rate as reported back in the trial, it’s usually reported as episodes per hundred patient years, and I can’t remember the exact number, but it was somewhere in the range of about 50 or 60 episodes per 100 patient years. So what that meant is with state-of-the-art intensive therapy in a, you know, very carefully monitored clinical trial back at that time—back in the 80s and early 90s—that people who were in the intensive group would have on average an episode of major hypoglycemia a little bit less than every two years, which in today’s world would be shockingly unacceptable because as we now move forward and just sort of move in today’s world and think about what clinical trials might tell us in type 1 diabetes with intensive therapy with all of the monitoring devices we have and with all of the better insulins, you know, we typically think about a rate of 2, 3—somewhere in that range—certainly 1/10 or less than what we saw back then. So the rate of hypoglycemia was very significant back then and clearly balanced all the positives.
DS: And before you finish this segment on hypoglycemia is there any data about any long-term sequelae from hypoglycemia in the sense of impact on cognitive status, dementia, or any other long lasting effect as to patients who did have hypoglycemic events as you described?
JL: Well, that’s a hard question and I’m not sure how to exactly answer that. I’m not sure whether there are any reported data from this trial on that specific issue. If there are I can’t answer that. And I think in some respects we have more of a general concern. I think all of us in this business of seeing people who have had repeated bouts of hypoglycemia and have had probably some medical and/or neurological sequelae related to that. On the other hand, I think that the prevailing opinion would be just the opposite: that people tolerate bouts of serious hypog  lycemia pretty well. We do know that there’s a relationship maybe with dementia in the diabetes world, probably more [with] type 2 diabetes. I don’t think that’s related to hypoglycemia, but on the other hand I guess one could argue a little bit we don’t exactly know, and there was great fear years ago that if you look at children with type 1 diabetes and do IQ tests they seem to be a little bit less good than control children, but on the other hand, if you now do studies against other children with chronic illnesses they kind of match up. So I guess my feeling in the answer to that is it’s never desirable to have any kind of significant hypoglycemia problems in patients, but it is not clear to me there’s any lasting sequelae in those patients.
DS: Right, and that’s my understanding as a primary care doc as well regarding both in general and as it relates to this trial that they did not find [lasting sequelae] specifically in the hypoglycemia group.
JL: Yeah, if I might, let me just actually jump in with one more thing if I might because there is another part to the trial related to hypoglycemia I probably should identify. So if you actually go back and read that trial because of this increasing rate of hypoglycemia in the intensive therapy and again a three-fold increase in the intensively treated patients. If you actually look at the New England Journal paper there’s an interesting figure, which is showing the benefits in terms of microvascular reduction as graphed against the risks of hypoglycemia when your x axis is the hemoglobin A1C. So the conclusion of that study was the optimal hemoglobin A1C in a patient with type 1 diabetes was 7 because then you have near total reduction in risk of retinal disease as opposed to less of a risk of serious hypoglycemia than if you further lower the A1C. So, back then we were pretty comfortable: shoot for 7, don’t go much lower, you know, do the best you can. I think in today’s world probably the discussion is not quite so absolute because our current insulins are a bit safer and actually the EDIC trial again has sort of raised some issues: maybe a bit lower is better.
DS: Right….Well, Jack, I really want to thank you. 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