The Diabetes Control and Complications Trial: Weight Effects

 Dr. Doron Schneider and Dr. Jack Leahy discuss what The Diabetes Control and Complications discovered about weight issues and the Diabetic patient.




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.
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.
DS:  Well, what a wonderful intro to the trial. [Y]ou 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. If we can spend just a few moments talking about each one of those. Let’s start with hypoglycemia. It was a pre-specified endpoint that was collected prospectively. What did we learn about really driving down that blood sugar to a mean of 7? What happened to hypoglycemia?
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. 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. It was clear intensive therapy back then came with a significant price in terms of hypoglycemia.
DS: Right. So let’s move now on to weight: what happened over the course of DCCT? And then we will talk about the extension trial in a moment. That, I believe, was one of the other major costs, if you will—correct?
JL: You are exactly correct. Everything I’ve said so far at least in terms of the risk of hypoglycemia was predicted. I mean, no one’s going to be surprised that when you lower A1C dramatically in these patients that, sure, hopefully, you would see benefits, which they did, but it’s going to come with a cost, and the cost was 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 starting 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: Well, Jack, I really want to thank you for that review. 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.