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Melanie Cole, MS (Host): Welcome to UF Health MedEd Cast with UF Health Shands Hospital. I'm Melanie Cole. And today, we're highlighting screening for type 1 diabetes in the primary care setting with Dr. Michael Haller. He's a Professor and Chief of Pediatric Endocrinology at the University of Florida College of Medicine.

Dr. Haller, it's a pleasure to have you join us today. I'd like you to start by explaining the various methods and tools that you use to screen individuals for the risk of type 1 diabetes. What are some of those key indicators and risk factors?

Dr Michael Haller: Thanks for having me on today, Melanie. So, screening for type 1 diabetes has become a really important topic, because it's a very common childhood disease. It affects nearly one in every 300 children in the United States. And really, prior to the 1980s, we had no good way to predict the disease. And prior to just last year, we had no good way to interdict the disease or to provide a therapy.

But we now do have tools for both of those things. And so, the primary way to screen for type 1 diabetes remains checking the blood for autoantibodies. And one could talk about doing that just in first-degree relatives where the risk is as high as 1 in 15, but we're moving into a time where it's justifiable to screen the general population, so where that risk is 1 in 300.

Those main antibodies, there are five of them: islet cell autoantibodies themselves, zinc transporter 8, glutamic acid decarboxylase autoantibodies, antibodies to insulin and IA2A or insulinoma-associated 2A autoantibodies. And most labs offer a type 1 diabetes autoantibody panel, or they can be measured or ordered individually. But the best way to do this is to certainly get all of them at one time. We now know that patients who have two or more confirmed autoantibodies have type 1 diabetes, whether or not they have any clinical symptoms.

And that's brought forward this idea of staging for type 1 diabetes. Where stage 1 is, in fact, the presence of those two autoantibodies. Stage 2 is the presence of two autoantibodies and dysglycemia, not yet to the level where one requires the use of insulin or has met the ADA definitions of clinical diabetes. And then, stage 3 being what we classically called type 1 diabetes when it presented in diabetic ketoacidosis and the patient needed insulin that day.

And so, screening with those autoantibodies now really affords us the opportunity to identify patients years, sometimes even decades, before they have clinical symptoms and offer them follow up that prevents diabetic ketoacidosis. And now, we can even offer them intervention therapies as well.

Melanie Cole, MS: Thank you so much, Dr. Haller, for that. Now, I'd like to speak about the current FDA approved therapies. Provide us a little bit of an overview. Are there any therapies aimed at preventing or delaying the progression of type 1 diabetes and how effective are these treatments?

Dr Michael Haller: We are now at the infancy of abilities to intervene and prevent type 1 diabetes. Prior to the late fall of 2022, we really hadn't had a paradigm shifting approval in the type 1 diabetes space prior to the discovery of insulin itself back in 1921. We've gotten much better at taking care of diabetes, and the technologies for managing diabetes have really improved dramatically and continue to do so at record pace.

But it wasn't until late last year that teplizumab, that's the generic name, or Tzield, the trade name, was approved for the delay in prevention of type 1 diabetes. And to date, it is the only drug to have received a label in this space. And it's a really remarkable drug. To use a baseball analogy, for the last 40 years or so, when people have been trying to intervene in type 1 diabetes, we had been effectively striking out. And we're by no means hitting home runs now, but teplizumab at least gets us on base for the first time, and that's a really meaningful thing to patients.

This drug, which is a cumbersome and expensive thing to go through, it's a 14-day IV infusion. And it has a retail cost of almost 200,000, so it's not trivial to get approved, but it can be obtained. It provides a two to three-year on average delay in progression to stage 3 diabetes in patients who qualify for treatment.

And while may ask yourself, is a two to three-year delay worth that cost and that time commitment? Ask that question to any family who lives with a child with type 1 diabetes, and they will be unequivocal in their answer. That is clearly a huge and tremendous move forward for the field, and it's a big important thing for patients and families to at least have that opportunity. There may be some families who very recently declined to move forward with teplizumab, and they want to wait for something better or something different where they may not want to consider immunotherapy at all for any number of reasons. But it is something that we should offer to patients and families. And the only way to know that they are eligible for the drug or to qualify is to start by getting them screened.

And so, that's why we're now in this new era. Whereas before, we used to recommend screening for autoantibodies really only in a research setting, it's very reasonable now to consider screening for type 1 diabetes autoantibodies in a clinical setting as well.

Melanie Cole, MS: Are there specific patient profiles for whom this is indicated or contraindicated as you talk about the patient profile, as you talk about screening for these autoantibodies? Tell us about patient selection for this drug you're mentioning.

Dr Michael Haller: Sure. So, the studies that got teplizumab approved were done in patients between the ages of eight and 50 years of age who had two or more confirmed autoantibodies and had dysglycemia on an oral glucose tolerance test. And so, that's the basis of the FDA approval, and is therefore the patient population for which you'd want to consider the drug. We don't yet have data for children younger than eight, although we would still recommend screening them because we have other research studies to offer them, and they may still be in stage 2 when they reach the age of 8, so they may have a reason to be screened earlier and then be eligible for the drug on-label as they get older.

 And many people in the clinical world are using other tools to identify folks who have dysglycemia beyond the sort of more cumbersome five-point oral glucose tolerance test, although that is what the data that was done in the clinical trial were dependent on to demonstrate that these folks had dysglycemia.

So in general, you're looking for folks in that age range, eight to 50, but you've checked autoantibodies on, they're positive, you confirm that they're positive with a second screen, that is important to do, because the antibodies are not perfect. But if you have two confirmed on more than one test, that's definitely meeting the definition of at least stage 1 diabetes. And then, if you've confirmed that they have dysglycemia, they really do fit the population that was studied through the NIH-funded Type 1 Diabetes TrialNet, the results of which that study were, or what was used to get the label from the fDA.

Melanie Cole, MS: Dr. Haller, how do personalized treatment plans and precision medicine factor into the management of risk? I'd like you to speak about some of the key challenges and considerations when enrolling individuals into research studies for type 1 diabetes and how you can help healthcare providers to identify suitable subject for these studies.

Dr Michael Haller: We're also right on the edge of really being able to apply personalized medicine approaches to this population. And teplizumab is not a very distinct therapy that's targeted. It's still pretty broad in that it's just is a depleter of T cells. It's a monoclonal antibody to CD3, the marker that's on T cells. So, it just depletes all T cells, essentially. does so for a short term. It's a monoclonal antibody, so it's quite clean. But it induces some significant, although short term, immunosuppression. And it can result in infusion reactions like cytokine release.

So, when talking to patients and families about, you know, what's involved, those kinds of issues are going to dictate who's really a good candidate or not. And if you have a patient who unfortunately has high risk for type 1 diabetes, but also has known immunosuppressive problems or has immunodeficiencies, then teplizumab may not be the optimal drug for them.

And then as we're moving forward, what we're trying to do is look at the detailed results from the studies where we've used teplizumab and other immunomodulators to see that not all patients are what we call responders. Even though, on average, the drug delayed progression by two to three years, that's not true for every individual patient. And about a third of the patients were non-responders, meaning they progressed to stage 3 diabetes just as quickly as those who were receiving placebo in the research studies. So certainly, if you're a parent or a family member and you're considering teplizumab, you would want to ideally know if your child or loved one is likely to be a responder or non-responder.

And so, we're currently using advanced immunological studies, genetic mapping to try to better identify who patients are that are likely to be responders before we expose them to these drugs. And we're still frankly learning how to do that well. So in today's day and age, it's really still just trying to say, does this patient qualify based on their baseline demographics of being in the right age, of having dysglycemia, of having multiple antibodies, and then being willing to take that risk of being a responder or not.

Hopefully, in the next few years, we'll be far more able to be discreet about that and tell people, you know, "Teplizumab's not the right drug for you because you're not likely to be a responder to this, but perhaps maybe we can offer you drug X, Y, or Z because you do have a particular immunophenotype that suggests you'd respond better to those other options."

Melanie Cole, MS: Dr. Haller, I'd like you to tell us any promising therapies that you see in the future, any novel diagnostic methods that have the potential to advance our understanding of type 1 diabetes.

Dr Michael Haller: Yeah. So, we have so many things in the pipeline within Type 1 Diabetes TrialNet right now where we have studies for newly diagnosed patients with stage 3 diabetes. Right now, we have a combination therapy approach using two drugs that individually have demonstrated benefit. Those drugs being rituximab and abatacept, both immune modulating drugs with different mechanisms of action than teplizumab, both that have shown that they can preserve some beta cell function in newly diagnosed patients. And so now, we're going to try them sequentially in newly diagnosed patients to see if that can create some synergy and expand on that benefit.

We have another new onset study that's available to children as young as eight using a category of drugs called tyrosine kinase inhibitors. So, those are oral agents which have been used for many other immune modulating diseases in the past. And so now, we're trying to apply those to type 1 diabetes as well.

And then, there are options for immunotherapeutics that are outside of the confines of a research study, but are off-label. And much of what we do in pediatric care is off-label, largely because the pharmaceutical companies don't necessarily want to fund the expensive and long studies that are required to get that FDA label. One example of this is a drug that's been around for many decades called antithymocyte globulin or thymoglobulin. And that's a drug that is commonly used in kidney transplantation and treatment of transplant rejection. Our group and many others have been studying low doses of thymoglobulin in type 1 diabetes and have shown that, at least in newly diagnosed patients, it's as effective as teplizumab. And because that drug is only a two-day infusion, and as a cost that's two orders of magnitude cheaper than teplizumab, it is a real and important consideration for families who are looking for alternatives when they may not qualify for teplizumab or may not want go through the 14 days required.

So, there's lots of exciting things going on in the research world. There's lots of other opportunities in the clinical pipeline, and I would say that while we're far from getting runner on first base all the way to home and having something that's a real meaningful biological cure to type 1 diabetes, we are certainly making important progress on our mission towards achieving that goal someday.

Melanie Cole, MS: Dr. Haller, this has been such an informative episode. As we wrap up, I'd like you to speak to other providers about how you approach counseling patients and their families about the genetic and hereditary aspects of risk and describe the importance of this multidisciplinary care teams in the management and how different healthcare professionals collaborate in the context of type 1 diabetes.

Dr Michael Haller: The challenges are really how to apply this in a public health manner that makes sense for practicing pediatricians and family practice docs and internal medicine physicians out there without swamping them. We can't expect everybody to be an expert in type 1 diabetes. That's how I spend my day, but these providers spend their day taking care of thousands of other diagnoses.

So, what we need is for those docs to have at least enough comfort and understanding to screen their folks who are high risk. Undeniably, they should be screening anybody who has a relative with type 1 diabetes. That is a no-brainer and everybody should be getting that 5 autoantibody panel for those patients. They can do that through their clinical lab, or they can do it through TrialNet for free if for some reason the patient doesn't have insurance coverage.

And then, I think the more nuanced conversation is about screening general population patients. And even there, I think there's a strong argument for doing that for families who are interested in the information, who might be willing to take on intervention or participate in a research study if they find that their child has autoantibodies. And so, it requires a big team effort. Because once those patients are identified, we need them to be referred to type 1 diabetes specialty centers like ours at the University of Florida so that we can help co-manage the patients, we can educate them on what to expect with their child's progression towards type 1, and offer them participation in any number of research studies. And then if they're not interested in those research studies, be able to warmly hand them back to the primary care providers and still arm them with the information they need to make sure that they don't miss a rapid progression of type 1 diabetes so that we can end up in a world where no child, if they unfortunately have to live with type 1 diabetes, comes into the hospital with diabetic ketoacidosis at diagnosis, which still in today's world occurs 35 to 40% of the time in newly diagnosed patients. When we know when those folks are in studies where we follow them, we can get that rate down to less than 2 or 3%.

So, that is an entirely fixable problem that requires a team approach where primary care docs and, you know, type 1 specialists like our team can work together and get the word out, so that we can eliminate diabetic ketoacidosis, at least until we have something better to offer for folks to eliminate type 1 diabetes entirely.

Melanie Cole, MS: Thank you so much, Dr. Haller, for this educational and informative episode and for sharing your expertise with us today. To learn more about this and other healthcare topics at UF Health Shands Hospital, please visit innovation.ufhealth.org. And to listen to more podcasts from our experts, you can always visit ufhealth.org/medmatters.

That concludes today's episode of UF Health MedEd Cast with UF Health Shands Hospital. I'm Melanie Cole. Thanks so much for joining us today.