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Steve Freed: This is Steve Freed with Diabetes in Control and we’re here at the American Diabetes Association 77th Scientific Session 2017. We’re here to present you some really exciting interviews with some of the top endos from all across the world. We’re going to start off with a very special guest. A gentleman, a doctor, who if you don’t know who he is, then you shouldn’t be involved in diabetes. Dr. Ralph Defronzo. I have to say it’s a real pleasure to have you here today.
Dr. Defronzo: My pleasure.
Steve Freed: It’s exciting for me just to be able to sit across from you and pick up your knowledge to make me a better diabetes educator.
Dr. Defronzo: This will be a fun interaction, I’m sure.
Steve Freed: Maybe we can start with, tell us a little bit about yourself.
Dr. Defronzo: I’m a professor of medicine and chief of the diabetes division at the University of Texas, Health Science Center in San Antonio. I also serve as the Deputy Director of the Texas Diabetes Institute, which is the largest center in the U.S. for taking care of people with type 2 diabetes. We see about 10,000 unduplicated patients every year. It’s a largely Hispanic community. It’s an underserved community. Our center is in the heart of the Hispanic community. We do a lot of community work in addition to just taking care of our diabetic patients. We have a lot of outreach programs to improve quality of life, make it healthier for them. It’s a pretty well-integrated, academic, clinical community.
Steve Freed: How many papers have you been part of?
Dr. Defronzo: I think I passed 750 publications this month.
Steve Freed: It seems like everybody wants your name on their studies. You’ve been involved with so much, the knowledge that you’ve gained. Going off of script a little bit, if we go back 50 years, and we bring it up to today, what has been the major change that you’ve seen?
Dr. Defronzo: When I first started, even if you think back to 1995, we had two drugs. We had sulfonylureas, which now we consider them pretty barbaric, and insulin, and that was it. I actually was the person who was responsible, to get Metformin approved by the FDA. That happened in 1995. We thought, “man, we’re in heaven now, we have two drugs. We have Metformin and sulfonylureas.” Then you think about all the drugs that we have now, how much better off patients’ lives are and how much easier it is for doctors to get people under control. The big problem now as I see it is affordability of many of the newer medications, which work really quite well compared to the older medications but are also quite expensive. This is an issue that we all have to deal with as physicians.
Steve Freed: One of my major questions for you is they’re going to present a lot of new information here. What, is the most exciting information that you believe is going to be coming out of this meeting?
Dr. Defronzo: Well, I think we’re going to see a lot more about the cardiovascular outcome trials. I think that this has now made in my opinion a significant change that I hope we’ll force HMOs, insurance companies, now to move the newer drugs up. So we’ll hear a lot more about the EMPA-REG Outcome Study. If we have a medication that decreases significantly the MACE endpoint and particularly decreases mortality by some 38% to 40%. I think we need to think more seriously about putting these drugs up as first line therapy. We have a lot more that we’re going to hear from the LEADER trial and from SUSTAIN-6. Again, the GLP-1 receptor class showing a decrease in cardiovascular events. We’ll hear a lot about another SGLT-2 inhibitor from the CANVAS study, canagliflozin. I anticipate that it will be positive as will be EMPA-REG, which will lend credence to the SGLT-2 class, not only as a very important drug for lowering glucose, but a drug that decrease cardiovascular events. To me, there are two big problems that diabetics have, the microvascular complications, eye, kidney, and nerve damage of course more are related to glycemic control, but the cardiovascular complications are what kill our patients, mortality. So if we have drugs that both effectively reduce glucose and decrease cardiovascular events. To me, those are the drugs that should be the front line drugs.
Steve Freed: You’re one of the first people to recommend triple therapy because you’re very aggressive with your treatment. One of my favorite questions that I always ask at the end but I don’t want to forget so let me ask you know is when you go downstairs into the display room, they’re going to be offering free A1C tests. You go there and they stick your finger and they get a drop of blood. In a few minutes they get a result on a piece of paper. They’re going to hand it to you and on there there’s going to be a number. It’s not going to say “below 7”, it’s not going to say “between 5 and 8”, it’s going to be a specific number with a decimal place. If you can have any number, regardless of your health, if you can have any number, what would you want your number to be for your health?
Dr. Defronzo: I would like it to be somewhere between 5.0 and 5.4. A1C is a very useful test because you can get it any time, even if the person is not fasting. So that means, we do a lot of screening, people can just walk into the clinical research center and you don’t have to have them fast it overnight. You don’t have to do an OGTT. But there’s also a problem with the A1C. Of course if it’s markedly elevated you know you have diabetes. But there’s an intermediate range. We’re looking at a 5.7 to 6.4. So we have this term prediabetes. It’s a term that I don’t like because you can either have impaired glucose tolerance, which means an elevation in the two hour glucose during OGTT or you can have impaired fasting glucose, which is an elevation in the fasting glucose. Of course you could have both. So the A1C doesn’t tell you which of those two disorders you have. They’re very, very different disorders. Impaired glucose tolerance really is the metabolic syndrome. These people have severe insulin resistance in muscle. They have a marked decrease in second phase insulin secretion. IFG, on the other hand, impaired fasting glucose, [is a] very different disorder. This is insulin resistance in liver and loss of first phase insulin secretion. It’s not really associated with a metabolic syndrome. You get an A1C and let’s say it’s 6.1. You know something’s wrong. But you need to delve further. Am I dealing with impaired fasting glucose or am I dealing with impaired glucose tolerance? Or combined? I believe that these disorders, because they have different pathophysiologies, should be treated differently. We have a very large study that’s going. Initially funded by the American Diabetes Association, now to look more carefully at what would be the best treatment for these two different types of disorders. Now, if you’re normal and you’re 5.0 or 5.4 you don’t have to worry about it. But if you’re in that grey zone then I think you need to know a little bit more and then of course if you have an A1C of 8, you know you have to do something in a more serious fashion.
Steve Freed: You were one of the first to use triple therapy. Certainly a more aggressive attitude. Now we have drugs that actually prevent or reduce your risk for death. Now we’re coming out, we’re finding out the SGLT-2s may cause amputation of your toes. It may cause other issues. I don’t think there’s a drug on the planet that doesn’t have side effects. But we’re not going to die from the loss of a toe. What are your thoughts even when it comes to SGLT-2s? I know they’re fairly expensive right now. Competition hopefully will reduce that. What are your thoughts about the SGLT-2 drugs and the GLP-1s?
Dr. Defronzo: Let me just back up before I talk about this amputation issue, because it’s going to be very controversial. To me, I’ve always been a strong believer that you need to understand what causes type 2 diabetes. NIH spends millions and millions of dollars to help us try to define what causes the disease. If you know what causes the disease, you ought to use medications to reverse the problem. Sulfonylureas clearly don’t do that. In my opinion, these drugs, other than cost, really should not be being used in our diabetic patients. We have much better armor material. So if I had to list the drugs, and this may be a little bit different from what other people tell you. I would put a tie between GLP-1 receptor agonist and pioglitazone. And very close to those two, I would put SGLT-2 inhibitor. I’d put Metformin as a good drug but lower down. Those are my four good drugs. Then way down, I’d put DPP-4 inhibitors and I just don’t use sulfonylurea drugs. I don’t believe that there’s any need for these drugs. You’d have to be very hard pressed that people could not afford any other drug before I’m going to resort to using sulfonylurea drugs. We’ve done a very large study with triple therapy. It’s now into its 5th year. We use a combination of pioglitazone, a GLP-1 receptor agonist, and Metformin. Because when we started these studies, SGLT-2 inhibitors were not around. I can tell you now, the results are phenomenal. These people have three years later normal beta-cell function. They have a 60% improvement in insulin sensitivity. They lose weight. There’s minimal hypoglycemia. We just published a very large study in Diabetes Care, it’s called the Qatar Study, where they’re going to play the World Cup. We took people who had failed completely on Metformin and sulfonylurea. Their A1C was 10.1. They had ten and a half duration of this disease. We added a GLP-1 receptor agonist plus pioglitazone. A year and a half later, they have an A1C of 6. So, the beta cells, I’d rather say, they’re not dead, they’re hibernating. People don’t recognize that the TZDs have a huge effect on the beta cell. GLP-1 receptor agonists have a huge effect on the beta cell. And then pioglitazone also has a good insulin sensitizing effect. If I had to do this study over again, I actually would replace the Metformin with the SGLT-2 inhibitor. But these are all good drugs and docs need to learn how to mix and match them. Then they also need to remember that even though you start on two or three drugs, or even you start on one drug, you need to follow the patient to see what happens. If you get a gratifying response, great. But if you don’t, then you need to move on quickly, either adding one or two additional drugs.
Steve Freed: Now, you had mentioned, if you go back 50 years, we had one oral drug. Today, we have a couple million possible combinations if you include insulin in there. What you see coming down the pike as far as the future because it used to be simple. You go to your doctor, and he gives you a prescription for sulfonylurea. Today, there’s so many options and so many new drugs that each of them has side effects. They’re all a little bit different. They’re certainly better than what we had. How do you teach a physician, what possible combination he should use? Is it just trial-and-error?
Dr. Defronzo: Well, I think for endocrinologists, it’s a little bit easier because this is our job. I think the real problem is amongst primary care physicians because they have to learn all of these new diabetes drugs. Then they have G.I. problems. They have to learn all of these new G.I. drugs. Then they have people presenting with arthritis and collagen vascular disease. Then we have this whole new plethora of immuno-suppressive drugs. I feel sorry in a certain way for the primary care physician because he’s supposed to be an expert in everything. Well, that’s not possible. The good part is we have very good medications. So that’s an advantage. Sometimes I see patients coming to me, I wonder why are they on these drugs when they’re not well controlled, when there are better drugs. It sounds easy for us. I see a patient literally in 10 to 15 minutes, I can handle all the problems. I know instantaneously what to do with glucose, lipids, blood pressure, and cardiovascular issues. That’s basically the major part of diabetes cardiovascular hypertension treatment. And since I’m board certified in nephrology as well, I know if they get kidney problems what to do. So for me it’s very easy to take care of diabetic patients. It’s not so easy for primary care physicians and then on top of all of that, we have cost. These newer drugs are really quite expensive. Also, if you prescribe a drug that’s not on the patient’s formulary and he goes to pick it up and it’s $500, believe me you haven’t prescribed any drug, because he’s not going to get it. Even though, the docs may understand what drugs do and what are the good ones, not always can you prescribe them for your patients.
Steve Freed: So let’s talk about prediabetes. That’s a fairly new term. Obviously like you said, you don’t really like it because diabetes is diabetes. It causes damage even 5.7 in some ways. It may take a little longer but it’s still causing damage. So what would you like to see happen besides, it’s strange that the ADA can recommend Metformin, the FDA doesn’t even have any recommendations for prediabetes. That makes it tough for insurance companies because you can’t give them the drugs for diabetes, you can only give them Metformin. That’s a $3 drug to begin with, so that’s not a big deal. So what are your feelings about that?
Dr. Defronzo: So I was part of the Consensus Conference of course, many years ago that said that if you’re a high risk person, and particularly if lifestyle intervention didn’t work, you should consider putting the people on Metformin therapy. Unfortunately that’s not a drug nor is there any drug that is approved by the FDA. The FDA has sort of held fast that if you’re going to have a drug to treat prediabetes, you’re going to have to show a benefit in cardiovascular events. To me, that’s not appropriate. First of all, if you started the prediabetic state, you’re going to be 10 or 15 years before you’re going to be able to show a decrease in cardiovascular events. You’d need a huge number of patients. Probably 20 to 25,000 patients followed for 10 years before you’d show a statistical difference. So, what pharmaceutical company is going to do a 10 year study with 20,000 patients? I think that there needs to be a reassessment of this issue. The ADA needs to be at the forefront. The ADA, in my opinion, needs to take a stance and then say that it’s important to identify high risk patients with “prediabetes” and that they should encourage the FDA to do trials for preventing progression of prediabetes to diabetes. For the simple reason that if your glucose level doesn’t go up, you do not develop the microvascular complications of the disease. I don’t buy to the stance, just, let’s wait till the person develops diabetes and then we’ll treat them. While you’re waiting, you’re losing beta cells. That’s issue number one. Issue number two is just because you have the patient when they have prediabetes, you’re not going to follow that patient for the next three or four years to find out when they develop diabetes. These people get lost. So where I live in San Antonio, I have Mrs. Hernandez, she comes to see me. She is this “prediabetic state”. Her A1C is 6.3. I do an OGDT, and her glucose is 180. “Mrs. Hernandez, what about your mom and dad? Do they have a history?” “Oh yeah, my mother has diabetes.” “Any brothers or sisters?” “Yeah, I’ve got five brothers and two sisters.” “Any diabetes in the family?” “Oh, yeah, both my brothers and a couple of my sisters.” That person has diabetes. They’re going to get diabetes. The magic number two hour glucose 200. I don’t need to wait till they get there. This person has diabetes. I’m going to treat them. Now, we do have the option of treating off-label, but of course that makes physicians a little bit nervous. Nonetheless, when you have a person of Hispanic descent, the gestational diabetes, the components of the metabolic syndrome, family history of diabetes. They’re overweight. They got diabetes, pathophysiologically. They just didn’t reach that magic cut-point that the ADA says they have diabetes. I think these people should be treated and I think they should receive pharmacologic treatment with the intent of preserving their beta cell function and preventing the A1C from going up to a level where it could potentially inflict damage on tissues and lead to development of microvascular complications.
Steve Freed: Let’s assume that you had type 2 diabetes and your A1C was 5.8 and obviously you’re a physician, you can treat yourself with whatever you wanted. How would you treat yourself?
Dr. Defronzo: I actually would go on triple therapy. Now, when you say, it would be a little unusual to say that I had diabetes with an A1C of 5.9. That would be a very… you don’t see many of those type of patients. It could happen. You do the OGTT and the two hour glucose is greater than 200. Because your fasting is normal the A1C stays at 5.9. A more reasonable type scenario is you have the patient who is 6.4 or even they’re overtly diabetic. Their two hour glucose is 240. I personally would go on triple therapy. I would take a GLP-1 receptor agonist. I would take probably a low dose pioglitazone with Metformin or with an SGLT-2 inhibitor. I would be on the triple therapy right from the beginning because we know it works. We’re now five years into this triple therapy study and these people are very, very well controlled. They basically have normal beta cell function, major improvement in insulin sensitivity. This study has been initially funded by the ADA and now by the NIH, so we’ll have 6 years of follow-up. We’ll continue to follow the people whether we get funding or not. At some point if you have a strong genetic load from your parents, I think that drug therapy might not for the rest of your life keep you under control. On the other hand, if you have just a modest genetic load and you keep your weight normal and exercise, then I think you can maintain normal A1C for the rest of your life. Now, it still means that you need to follow people. There are people who, even though you treat them well, at some point in time, the diabetes can recur. We know this from bariatric surgery. These people have dramatic remissions. Then we follow them up and we start to see 5 to 10 years later the diabetes coming back. You can’t get rid of your parents. Your parents, whatever they did together that night, they created you, they gave you some genes and if you get a bad gene pool, you’re stuck with those genes. You’re going to have to be on medicines, you’re going to have to be followed up.
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.
Steve Freed: I love talking to you because I really respect what you do and your knowledge.
Dr. Defronzo: Well, thank you.