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Dr. Ralph Defronzo talks with Diabetes in Control Publisher Steve Freed during the ADA 77th Scientific Session in San Diego about the effects of certain medication on beta cell preservation and regeneration.
Dr. Ralph Defronzo, MD is Professor of Medicine and Chief of the Diabetes Division at the University of Texas Health Diabetes Center in San Antonia, Texas. Dr. Defronzo is also Deputy Director of the Texas Diabetes Institute.
Transcript of this video segment:
Steve Freed: One of the questions that I wanted to ask you is about regeneration of beta cells. If we get rid of the glucose toxicity and normalize blood sugars. Do we see that happening or is it the drugs like the GLP-1s where we’ve seen regeneration. Is it both, is it a combination?
Dr. Defronzo: I think that most of the defect that you see is a functional defect in combination with the loss of beta cell mass. Even if you look at people with “prediabetes,” probably you’ve lost somewhere between 10 or 20% of your beta cell mass. As your diabetes goes on you lose more and more of your beta cell mass. It’s critical that you prevent that. If you’ve lost 80% percent of your beta cell mass, now you’re like a type 1, you’re going to have to go on to insulin therapy. Insulin therapy is not the easiest thing in the world. It actually is quite expensive. There are going to be discussions about why insulin is so expensive these days. Patients don’t like to prick their finger and then adjust the insulin dose based on the carbohydrate that’s in the meal, based on what their fasting glucose starts. My goal is to make sure they never get on insulin therapy. I’m going to be aggressive early on. I’m going to treat them with drugs such as GLP-1 receptor agonist. These drugs have a powerful effect. I don’t believe, in humans, that they cause beta cells to replicate. What I believe is that they stop beta cells from dying. I think those that are very good. I think that they markedly improve the function. So I’m going to have a good chance at maintaining the beta cell mass you have. Those beta cells are dysfunctional, I’m going to bring them back to the normal function. Pioglitazone does the same thing. It’s a powerful inhibitor of apoptosis and it markedly improves beta cell function. Those are direct effects of the drugs on the beta cell. A drug like the SGLT-2 inhibitor which, I mean I invented that class of drugs, from beginning to end. Those classes of drugs they work on the kidney and you excrete the glucose in the urine, when you do that the blood sugar level comes down. Then, we get to this concept that you’re talking about, glucotoxicity. So over the years we’ve shown that chronic elevation of the glucose causes severe insulin resistance. Chronic elevation in the glucose causes impaired beta cell function. So in the original studies that really documented this in people, we treated the people with dapagliflozin, we’ve shown the same thing with the other drugs as well. So, I don’t think there’s anything that is unique to any one of these drugs. You put glucose in the urine, your blood sugar comes down, there’s about a 35% improvement in insulin sensitivity. But in our hands, actually the number was a 98% improvement in beta cell function. So you get a doubling of your beta cell function. Those are indirect effects from lowering the glucose, whereas the GLP-1 receptor agonist and pioglitazone, TZDs, rosi as well, have direct effects to preserve beta cell function. Probably we can’t afford this triple combination. But it’s a very good combination. People have some sort of stigma against the pioglitazone but we know from PROactive, the main standpoint was significantly decreased. More recently, we now have the IRIS study. Dr. Inzucchi knew from PROactive that in diabetics there was a 47% decrease in recurrent stroke. He convinced the NIH to go ahead and do a very large study in non-diabetics who had either a stroke or TIA within three months. In IRIS, there was about a 27% decrease in recurrent stroke and cardiovascular events in non-diabetics. So, to me, there is an enormous amount of data out there that pioglitazone is very, very effective in terms of preventing cardiovascular disease. So we have pioglitazone, we already talked about the Empa-Reg and SGLT-2, we’ll hear more about CANVAS here. The DECLARE study is coming. We have GLP-1 with SUSTAIN and LEADER. These are drugs that are drugs that are not only controlling glucose and doing it on a long term basis, you’re not dying, having heart attacks or strokes. To me these are good drugs. The cost is an issue, I understand. Barring cost, these are the drugs that we should be using and I strongly believe we need to be using them in combination.
Steve Freed: Well, I don’t want to take much more of your time although I could sit here for days.
Dr. Defronzo: We could do it if you want. (laughter)
Steve Freed: I love talking to you because I really respect what you do and your knowledge. I’m just so happy you were able to participate. Thanks.
Dr. Defronzo: OK, My pleasure.