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 about what the trial is can you tell us a little bit about really what was the construct of the DCCT?

 

JL:  So this is a trial that was designed to deal with a really controversial question many years ago: 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? 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.     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.  

 

DS: Excellent. That does help frame out the trial design. 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 as it relates particularly to hypoglycemia and weight.

 

JL: 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. It was clear intensive therapy back then came with a significant price in terms of hypoglycemia.

 

What was not predicted and actually was a big shocker is that there also came with a substantial risk of weight gain. And if you go to the original trial—the New England Journal paper and just kind of quickly read—what you will see is that on average about a 5-pound weight gain (so, remember this is about a 6- to 7-year trial) in the conventionally treated patients as opposed to about a 10-pound weight gain or thereabout in the intensively treated patients.

 

So, when you first read that, I think you could sort of say, “Oh, well, you know it’s there, but it’s not stunningly huge.” So even though it was there, it was reported as an outcome. I don’t think people initially sort of appreciated that this is kind of much of an issue. And then star ting two years later: lots and lots of subgroup analyses, different kinds of papers, take this huge database and start to analyze it, and there was a paper published a couple of years later which I think really put this into a capsule that we had not anticipated. And that was they started to look at the weight gain in the patient population in quartiles. And so, there was a quartile of people who didn’t gain any weight, so, you know, they were fine with the intensive therapy. And then the opposite quartile the average weight gain was very, very substantial. I can’t remember the exact number, but probably about 20 pounds on average. And actually when you went to that quartile, not only were they gaining weight; they were also having manifestations of many of the metabolic issues we sort of link to weight gain, such as blood pressure increases, such as a more metabolic lipid profile. And for the first time I think people’s eyes opened up to realize well, wow, there maybe is some overlap between the metabolic background that we then had typically linked really only to type 2 diabetes. Maybe in some patients with type 1 diabetes there’s actually a similar kind of predisposition, which might be brought out through intensive insulin therapy.

 

Now we again move into today’s world, and that’s a huge topic of conversation now because our teenagers and young people with type 1 diabetes are getting bigger and bigger and are having more of the metabolic sequelae that one sort of thinks about with obesity and insulin resistance. It’s not unique to type 2. We’re seeing it more and more in type 1 diabetes. So that’s the other issue with weight. It’s really emerged years after the trial to recognize this is a major risk of people who are on intensive insulin therapy if they have the genetic predisposition to be at risk for that.

 

DS:  I can’t help but just have you comment, if you would, around the type 2 diabetic patient. [A] majority of new onset diabetes is type 2, and this was a landmark trial. Can we glean anything as it relates to an even larger population—as it relates to micro- or macrovascular—from DCCT or EDIC?

 

JL: So the wonderful way to answer that is “more or less”: more or less everything I just said can be applied to type 2 diabetes as long as you’re willing to be a little creative in terms of lining up the similarities.

 

So, as soon as the DCCT came out, and again that was in a New England Journal paper in 1993, I think the results were so widely and stunningly accepted that intensive blood glucose control, as possible that many years ago, was viewed as now the standard of care for type 1 diabetes. Fine. But immediately, the question became, “Does this have any relevance to type 2 diabetes?,” because, of course, the vast, vast, vast majority of patients around the world have type 2 diabetes, and also, you know, we didn’t use insulin quite the way for type 2 diabetes then that we do now so we didn’t quite think about intensive therapy the same way for type 2 diabetes we did for type 1. And then, of course, in older folks there was always fear about additional risks of hypoglycemia in terms of what that might mean for cardiovascular risks on and on.

 

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 reviewing the DCCT trial as it relates to the type 2 diabetic patient. 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 of the trials. We look forward to seeing you next time. Thank you, Dr. Leahy.

 

JL: Thank you very much.