Satish Garg, MD, an Endocrinologist at Barbara Davis Center for Diabetes, University of Colorado Denver, talks about a new hope for Type 1 diabetics.
Interview conducted by Ivanhoe Broadcast News in January 2019
How long have you been here at the Barbara Davis Center?
Satish: 31 years. I started the adult diabetes program at the Barbara Davis Center in 1988. They only had the pediatric side of course on the all campus on 9th and Colorado. I was recruited to initiate the adult part of the diabetes program for people with Type 1 diabetes. So, I started in ’88.
Type 1s, we grow up.
Satish: Well, that’s a good point. In fact, 75 to 80 percent of living people with Type 1 diabetes are adults, commonly known as a juvenile disease that commonly occurs in younger folks. Not true actually the total number of people living with type 1 diabetes in the U.S. is somewhere between 2 to 3 million, worldwide is about 30 million, but 80 percent of them are adults with type 1 diabetes. And thus, they are seen by primary cares or they are seen by not the Peds. That’s important fact to keep in mind.
They just didn’t know about insulin pumps and just really difficult to find.
Satish: That’s exactly the reason because most of them I said are cared for by primary care or nurse practitioners or extended providers not by the endocrinologist. Because they only feel for us, only 3,000 practicing endocrinologist in the U.S. and out of those we probably see patients less than half of the time. There is not enough for a total of 50 million people who have both Type 2 or type 1 diabetes in the U.S. now.
Give me an overview of what type 1 diabetes is and how it’s currently treated?
Satish: Let’s look at the global diabetes first. There are about half a billion people with diabetes known or unknown worldwide. Out of them, about 50 million are in the U.S. 90 percent of the diabetes worldwide is type 2 diabetes, and about 10 percent is Type 1 diabetes. A large number of about one third of the patients both with type 1 and Type 2 diabetes are undiagnosed, unfortunately. For example, even with type 1 diabetes, it takes a long time before the disease manifests. And thus, many people who are older might have prediabetes, but it’s just not diagnosed. That’s important fact to keep in mind. What is type 1 diabetes? It’s different from type 2 because there is an autoimmune destruction of the beta cells, which is in the pancreas. So, that destroys the production of insulin. You have no insulin in the body. Insulin is an important hormone that’s needed to live. You and I, who don’t have the disease, if you don’t have insulin, you’ll die. Before 1921, everybody with type 1 diabetes used to die, because we didn’t have insulin. It was only in 1921 nearly a hundred years ago; the insulin was first formed by Banting and Best and the rest is history. We now have patients who live 70, 80, 90 years of age because it has changed drastically in the past five decades how we manage diabetes. Just to give you the history, we used to manage with one or two shots a day. Because who wants to take injections? When I started to practice medicine or when I went to med school back in the ’60s and ’70s, that’s what we were taught. That you just gave one or two injections a day so that they don’t go into ketoacidosis but avoid hypoglycemia and manage diabetes. It’s only an important pivotal study that was done by an NIDDK, NIH called Diabetes Control And Complications Trial. It was done only in 1,441 patients with Type 1 diabetes, properly randomized, showed for the first time that if you manage diabetes intensively you reduce the complications rate by 60 to 70 percent, both microvascular disease as well as macrovascular disease. Microvascular manifests in blindness from the eyes, kidney failure, kidney disease and the neuropathy which is you don’t feel your limbs and things like that. Macrovascular disease is peripheral vascular disease, which requires amputations, heart disease, and stroke. Those are the two manifests. In those pivotal studies changed the landscape.
And that was in the early ’90s right?
Satish: 1993 to be specific. The study started in the late ’80s it concluded in 1993. The publication was in New England Journal of Medicine clearly showed that you reduce the complications by 60 to 70 percent. Since then, almost all of us now manage diabetes intensively. Namely, we tried to imitate what your body or my body who don’t have diabetes does. Give insulin basal amounts, small amount all the time. That’s a long acting insulin. Every time you eat you take a bolus insulin. That’s called multiple daily injections a day. Three, four or five injections a day based on how often people eat or you can use an insulin pump which has the same concept. It gives you require amount of basal insulin all the time based on the recommendations by the provider, and you take bolus based on your carbohydrate or protein and fat intake through the pump. But the concept is the same which is intensive insulin therapy can be used either as MDI multiple daily injections a day or CSII which is insulin pumps. Having attended that 99 percent of the world’s population, who require insulin therapy are actually using only multiple daily injections a day. Very small portion about a million people worldwide use some sort of insulin pump therapy because of the cost and lack of resources it’s not a viable option for the masses.
But either way the multiple daily injections or the insulin pump therapy whatever insulin pump you’re on, it’s a lot of work. This isn’t just an easy disease to control. And anything that can help us improve blood sugars better is beneficial.
Satish: Yes, there are two parts. One is taking insulin. Second is monitoring glucose. In you and I, when we don’t have the disease body’s beta cells sense the glucose levels every second. And thus give you the required amount of insulin needed based on your food intake or based on your fasting state. Whereas in people with diabetes, that option doesn’t exist. Thus, they have to poke themselves many times a day either through the finger sticks or normal for the past 10 years the whole field is moving towards continuous glucose monitoring. That’s the future. We have done the work for the past 25 years in this area have clearly shown that’s where the future is. In fact, in the U.S. 80 leading centers a study that is sponsored by Helmsley trust, and we are a major part of that. Clearly showed that in the past 70 years, there has been a 10 fold increase in the number of people who use continuous glucose monitors in these leading centers quote unquote in the U.S. It used to be about 5 percent, and now it’s 35 percent of people use continuous glucose monitors. In a center like ours, probably 70 to 80 percent of patients use some sort of a sensor.
And why has there? Before we get into the details of your study why has there been no oral drug. Why can’t insulin been oral? And why has there been no oral drug for type 1?
Satish: The simple fact when you eat meat, it is destroyed or it is broken down and is basically absorbed as amino acids and what have you in the body. Same as insulin. Insulin is a protein like meat. It’s a bunch of amino acids. Thus when you eat protein, it will be destroyed by the gut from the same organ which makes the enzymes, the pancreas. That releases those enzymes into the lumen of the G.I. tract, and it destroys. You’ll have to take lots and lots and grams of insulin as compared to in MG when you inject. Thus, any molecule that’s destroyed by the guy has to be injected unfortunately.
Tell me about this new drug that you’re studying.
Satish: This new drug. First of all, in all fairness, it’s not approved by the FDA yet. There has been no oral drug available for type 1 diabetes. I’ll show you a list of drugs that have been tried injectable or orals, only one has been approved by the U.S. FDA called Pramaletide or Similin, hardly ever used because it causes extreme nausea, vomiting and severe hypoglycemia. We used to have few patients, nobody uses it. There are seven other drugs people have tried, all have failed. This new category of drugs called SGLT 2 inhibitors, sodium glucose cotransporter inhibitors are the first class of drugs that do not require insulin for their action. Remember insulin is absolutely mandatory for people with Type 1 diabetes not for type 2 diabetes. All other drugs that we can talk about do not require insulin for their action. Sorry, they do require insulin for their action. But SGLT2 inhibitors are the only class of drugs that do not require insulin for their action. Number two, they act on the kidney. In you and I, when we eat carbohydrates or the liver puts out the glucose, that glucose is filtered through the kidneys. About 180 grams of carbohydrate or glucose goes through the kidney. Imagine if all of that was lost, we’ll be eating all day. But the body has a mechanism that 90 percent of it is reabsorbed in the proximal part of the convoluted of the kidneys and the remainder 10 percent in the distal part. That almost all the glucose that we eat and is filtered through the kidneys is reabsorbed. This drug blocks that mechanism of reabsorption from the kidney. You start losing calories or losing carbohydrates or losing glucose in the urine. Two advantages, it doesn’t need insulin for its action. People lose weight because now they are losing carbohydrate or glucose in the urine. And on top of that, they are able to improve the glucose control by insulin independent mechanism.
Are you only studying this in type 1?
Satish: No. This class of drug which is called SGLT2 inhibitors four are already approved by the FDA. But this particular drug because the company didn’t have enough resources, they only studied in type 1 diabetes. But now a huge program has been undertaken by another bigger pharmaceutical company which is now investing more than $1.2 billion to do it type 2 program, which is ongoing in the U.S. You can go to the NCT.gov and look at all the protocols that are ongoing. That’s the reason this drug was only evaluated for type 1 diabetes. But these class of drugs like which is also known as Jardias, all these are SGIT2 inhibitors already have been approved for type 2 diabetes but none of them by any regulators in Europe or any other part of the world or the FDA have been approved for type 1 diabetes. All of their use is off label use.
How many patients were in the study? And tell me how often they took it and what were the results?
Satish: There were multiple studies. The one that you are specifically talking about is called in tandem program. There were three basic phase three trials which is in tandem one, two and three. All the three trials have been now published in the literature. The first one to be published was in tandem three which is a study which was published in New England Journal Medicine was looking at how people would introduce this drug in real life. A standard dose of 400 milligrams of was used, and people were randomized in a double blind way, followed for the 26 weeks we clearly showed that there was a net clinical benefit. I want to introduce this new term because FDA, the regulators, introduce this new term that if you’re going to study this drug in type 1 diabetes, we want to make sure that there’s a net clinical benefit. Which was defined as number of people reaching target A1Cs’ of less than 7 percent, which is recommended by ADA or EASD along with causing no severe hypoglycemia or ketoacidosis. The study clearly showed that there was a two fold increase in the number of people reaching target A1Cs or also known as net clinical benefit without any increase in hypoglycemia or Ketoacidosis. Not only that, in this study and most other programs have shown people lose about 3 to 4 percent of their body weight. Which is about four kilos of body weight, which is placebo corrected weight loss. In addition, about 10 to 15 percent reduction in insulin dose. This drug has two components. Only drug in this family has a SGLT 1 and SGLT2 component. SGLT2 I’ve already described to you primarily acts in the kidney. SGLT1 effect is mainly on the gut. This is the only drug in this category that has a small SGLT1 effect meaning thereby, it reduces and delays the absorption of glucose from the gut. And thus, it reduces both span of hypoglycemia. A post meal rise in blood glucose one or two hours after the meal in addition to losing glucose from the urine. It has dual effect. That’s why this is the first drug to have dual SGLT 1 and 2 inhibition. It is a big deal. I’ll tell you why. Majority of the patients with Type 1 diabetes or insulin requiring patients with diabetes do not achieve target A1Cs. I’ll show you some slides. The data shows 70 percent of the people in the U.S. or any other part of the world, probably worse in the rest of the world do not achieve target A1Cs
Of all diabetics not just type 1s?
Satish: I’m talking specifically about the type one.
That number applies to type 1.
Satish: Not only are they not reaching the target A1Cs, if you look at overall population in the U.S. and even many other parts of the Western Europe 70 percent of the people have type 1 diabetes are getting overweight or obese, which was unheard of. That’s because we have moved on to intensive insulin therapy. That is a side effect of the cost you pay is weight gain. Increasing the risk of severe hypoglycemia, but you still don’t reach the target A1Cs. This drug clearly shows that now you might have an oral drug. Always adjunctive to insulin therapy. Insulin is not going to be stopped. This is very important for people to understand. This is only an adjunctive treatment to insulin therapy for people with Type 1 diabetes that will allow them to hopefully reduce their insulin dose. But at the same time, improve their glucose control, reduce the number of severe hypoglycemic episodes and have a significant number of people lose weight and thus the net clinical benefit should be to the patient.
And for the implication for the patients, if they can reach their target A1C, if they’ve got their blood sugars are in better control for more percentage of time, what does that mean? Does that mean less chance of complications? Tell me what that means for patients.
Satish: Eventually learning from DCCT Diabetes Control and Complications Trials where they actually were aiming A1C to be at 6.5, but they only achieved from 9.2 to 7.2 to percent in the intensively treated and showed 70 percent reduction. Today, the mean A1Cs in the U.S. or many other part of the world in a patient with type 1 diabetes is hovering between 8.5 to 9 percent. By reducing this down to 7.2 or in that range you will reduce the long term complications of diabetes, but more importantly without gaining weight. That is huge for patients. Our young people who were in these studies said boy, Doc. I’m melting away. I need this drug because they were losing weight at the same time they were improving their glucose control.
Was it just one pill a day?
Satish: One pill a day. 400 mg. One pill a day. There were other two studies one and two which have both been published in diabetes care in the last month’s issue clearly show the same. One was done in the U.S. I’m the second author on that manuscript, and clearly show exactly the similar results. Two which was done in Europe and Israel shows exactly the same results.
Any side effects?
Satish: Yes. That’s an important part to keep in mind. Nothing comes free. There are side effects that are well known. Because you’re losing more glucose in the urine, you’ll always have more genital mycardic infections. Fungal infections or maybe general infections. More so in the men because they have a smaller urethra.
Like a UTI?
Satish: UTI. Urinary tract infections or general infection. But that’s because more glucose is now present in the general area that’s known. Not a big deal. About 10 percent manifest that, but usually it can be handled. The number two is most people will have with this drug might have small GI side effect because remember I said this has SGLT1 inhibition, which is in the gut. Thus, they might get nausea, vomiting, diarrhea. But the effect is so trivial, very mild that hardly anybody discontinued. About two to three fold increase in the number of people as compared to the placebo who had actually GI side effects. But nobody discontinued the drug. Usually the side effect goes away after a few days. You can introduce, in real life, we’ll start with a smaller dose, get people used to it and then gradually increase the dose. And that’s the best way to induce so people can tolerate. But in these studies, even though we started out with the full those hardly anybody or very few people discontinued from the study. But the major side effect is ketoacidosis. There is an increased risk of ketoacidosis.
How is that possible?
Satish: That’s possible because when you lose so much of glucose in the urine, glucose is needed for the body, for the brain, for the heart. Now, body realizes that boy, I need to make more glucose. What are the sources do neoglucose Genesis making new glucose from the liver? What it does is it breaks down the fat and breaks down the protein and that goes through a cycle, a metabolic pathway and where it makes ketone bodies. If you reduce significant amount of insulin, especially basal insulin you have a high risk of ketoacidosis as compared to the placebo, the risk is about two to three fold higher than people who are on these drug. This is the class effect. The studies have been done with other two drugs all phase three programs, which is also approved for type 2 diabetes or Jadians which is have all been done and been published in diabetes and clearly show the similar side effect profile. The other two drugs do not have SGLT1 effect, but the predominant effect of even the is the SGLT2.
So how do you get over that? How do you combat that, the ketoacidosis?
Satish: This is very important because we need to first know; what is the background risk? The background risk for ketoacidosis in people living with type 1 diabetes, or those requiring insulin therapy, is about 4 to 5 percent. It’s similar to what happens in real life. However, as compared to the placebo in these studies was two to four fold higher. We need to find ways to mitigate this risk. One is people need to start learning how to check for ketones because nowadays most adults, as I said, most people with Type 1 diabetes, who are adults, don’t monitor their ketones anymore. Number two don’t focus as your treating the dose much on reducing the insulin dose. There is a reduction that’s going to happen because people lose weight, losing four kilos will have their insulin dose goes down. But that focus should be primarily on dose not the basal does. If you keep basal insulin dose about the same, you reduce the risk of ketoacidosis.
So you’re just reducing the bolus.
Satish: The Bolus insulin dose. Number three, which is very important is the carbohydrate intake. Nowadays, people do those paleo diets and all sorts of high protein diet. If you don’t eat any carbohydrate, you may have a higher risk of getting into ketoacidosis. The fourth, which is very important, that people will get a different kind of ketoacidosis with these drugs. It’s called Uglycemic or normal glycemic ketoacidosis.
So your blood sugar doesn’t have to be high.
Satish: Normally in diabetic ketoacidosis blood sugar are sky high. But with these drugs cause you’re losing carbohydrate glucose in the urine, the blood glucose may be normal or only mildly elevated. Thus if a patient manifests in a primary care office or goes to the E.R., they may not notice. We have lot of educational efforts that will need to be done to retrain people that you have to realize that there is a Uglycemic ketoacidosis. They would check ketones, that would be a requirement. They would check ketones.
You’d have to?
Satish: Exactly. Blood ketones is the best way to do. There are meters available that we have to retrain patients. There’s been there is a new protocol that I’ve just published it’s called STICH protocol. Stands first. ST stands for Stop. I stands for Insulin, C stands for carbohydrate, it (H) stands for hydration. If you follow the set protocol in trying to manage people who have gotten into decay and monitoring their ketones you can avoid going into the E.R. or the ICU setting.
Can you talk about the importance of that?
Satish: As I’ve said all along improving glucose control, and reducing long term complications should be our goal to date in the past 100 years. Ever since insulin became available only therapy for people with Type 1 diabetes is insulin or manage their glucose by having to finger stick. The new therapies of using continuous glucose monitors and different or new insulin analogs have helped. But have not really budged overall glucose control. Availability of an oral drug, oral tablet which can be added to insulin therapy without increasing any severe hypoglycemia and having them lose weight and improving their glucose control, it’s a big deal. To overall improve the long term outcome of people with Type 1 diabetes.
Is this one of the biggest breakthroughs you’ve seen in your career?
Satish: I think so. I think for people with Type 1 diabetes this may be the biggest breakthrough that they’ll see. But having said that we need to learn how best to manage ketoacidosis. This need to be taught to primary care, nurse practitioners, PAs and what have you. It’s not an easy deal because most adults with type 1 diabetes don’t monitor their ketones at all. They need to be retaught.
Are there more studies currently undergoing or underway or is this on its way to FDA approval or?
Satish: Sotagaflozin specifically has been already filed last March with the FDA and also with the European Union. Advisory committees happening in January of 2019, and the PDUFA date which is likely to be the approval is in March of 2019. The depagaflozin has been filed in the European Union. And I believe they’re in the process of filing for type 1 approval with the FDA. Same is true with Ampagaflozin, those studies were two and three which were just shown two weeks ago in Berlin at EASD, and they were also published simultaneously in diabetes care. They’re in the process of filing both to the European Union as well as to the FDA.
So we’re specifically talking about this drug. But this is a class of drugs.
Satish: This is a class of drug.
So these other drugs are there big differences between them?
Satish: No pretty much the same.
OK so the side effects?
Satish: 99 percent are the same. The only difference is Sodagaflozin has an SGLT1 effect which acts on the gut thus helping the post brand raising blood glucose. That’s the only difference. But 99 percent the drugs behave about the same in lowering their A1Cs, risk of ketoacidosis, loss of weight, which I’ll show you on the slide is pretty much identical.
END OF INTERVIEW
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