Emily Sims, MD

One of the things I think we should revisit in this discussion is the staging of diabetes. 10 or 20 years ago, there wasn't really staging at all. Either you didn't have type 1 or you did have type 1 diabetes. We asked Dr Sims to revisit that when she discussed it too. Type 1 staging is where you're antibody positive, but there are no symptoms, but there's also no change in blood sugar fluctuation. If you give someone a glucose tolerance test, they produce plenty of insulin still, but the antibodies are doing their magic and working against those beta cells. And then we have stage 2 where the antibodies are positive and yet during a glucose tolerance test that those blood sugars start to rise. And that was that first phase insulin response that she was discussing. That's the hardest time that you need the most insulin is when you eat carbohydrates. If you think about that as a clinician, that makes the most sense is that that would fail first and not the fasting blood sugar. When you think about fasting, the patient has had all night to make enough insulin to get that blood sugar down when you check it.

Diana Isaacs, PharmD, BCPS, BCACP, BC-ADM, CDCES: 

Can you tell us, I know when someone has 2 or more auto antibodies, what's the chance that they're going to develop type 1 diabetes?

Almost 100% in their lifetimes. And in the beginning, we thought about diabetes as something that came on as a child. It was juvenile onset for so many years. We have lots of patients who get it as a child, but we also have lots of people who get it as an adult. And you and I both have had patients in their 60s, 70s, 80s develop type 1 diabetes. How do we know how long they were antibody positive? We don't. But you have a 100% chance or close to it if you have two or more antibodies positive.

Yes. The staging system is interesting. There's not a ton of awareness about it. It's in the ADA standards of care, but I don't think a lot of people are aware of it. And especially in adults where type 1 diabetes tends to be more slow progressing, The staging is very helpful. For example, a common, I guess it's not so common, but I've experienced it in a number of my patients where a woman is diagnosed with gestational diabetes, right? And then come to find out, she actually has the auto antibodies. And I've seen several cases where the endocrinologist, someone thought hey, let's, you didn't seem like a person, you didn't have the characteristics that might put you at higher risk of developing gestational diabetes. Let's go ahead and check those auto antibodies. And sure enough, they've had them. But the neat thing about it is we've been able to catch it so early that in terms of the treatment, often we don't have to go straight to needing basal bolus insulin or using an insulin pump. When you catch it early, especially in adults where it's slower progressing, we can start off sometimes with even other therapies like with using metformin, but often maybe just with a long-acting insulin and not requiring mealtime insulin. It's interesting. There's a lot of benefits to this staging and to early detection.

Yes, and think about, when you think about diabetes, type 1 diabetes and the burden that comes with the management, the day-to-day management, every time you look at food, every time you think about how far is the gate that I walk to at the airport? Is that going to drop my blood sugar? What's going to happen next? There is a real burden that comes with this disease. Knowing ahead of time and using therapies as quickly as possible and addressing them as opposed to waiting will be a real option for patients.

I'm curious your thoughts on this. Of course there is a burden, but now we do have so many better tools, so many better technologies. We've got all these automated insulin delivery systems. I mean, I've got several patients that are easily able to get that 70-80% time in range. What do you think with all the new technologies, is it still as much of a burden? Do we still, should prevention or should cure? Is it still important?

I think it is. And some of the reasons are that we don't know. It's very hard sometimes. We can all talk about the patient, the person with diabetes who's had an A1C of 12 and they end up with eye disease, right? And those people that suffer and that they're trying to just get food on the table and trying to get their heat turned on a regular basis, their blood sugar sometimes can reflect those challenges in their lives. The social determinants of health when you, with type one diabetes are very similar to the social determinants of health with type 2 diabetes and the management of it all and the overwhelming feeling. So AID, automated insulin delivery, is still not for everyone. And I certainly, I have amazing patients who do very, very well. But I also have a lot of patients who really struggle, even with amazing technology that wasn't here 20 years ago, to get to goal and not feel like that's all they do every day. There is a place for delaying the onset. You could choose not to use the medication. We always want to provide a fair and balanced discussion. And this is a harder one because if you don't use the drug, there isn't another drug option. But you could just wait for the diabetes to come. And I don't know that we can always pick the patient that will suffer or have higher burden from the disease than other people. Because you and I both have those, we have both patients who seem to suffer a lot and who just struggle with the management, the daily management, and others who don't have that same challenge with it. They don't like it. They never wake up and say, there's a great diabetes day. But they also don't have the depression and some of the other things that kind of come with that wear and tear of diabetes daily.

Yes, I'm with you. I mean, I'm thrilled with all the different tools and the technologies we have. And I do tell my patients, I'm like, this is, if you must develop diabetes, this is the best time in history to have it because we have all these tools. But the reality is for automated insulin delivery currently, it does require wearing 2 sites. Your pump, you have your CGM, maybe at some point it'll be consolidated into one, but it's still wearing something all the time. And when you wear something, it's you have something on your body. If it falls off, that's a problem, right? You're not getting what you need. I agree with you. I think the cure, the prevention should still be a major focus. And I'm very excited to see that we are finally moving the needle on this. I mean, how many times have you heard a cure is five years away?

50 years now. Right? We've been hearing it for our whole careers. Right.

Right, and I don't know if the cure is 5 years away, but I know that we have gotten a lot closer. The fact that we can delay diabetes by a few years. And even the thing is, it's not just the delay. Because it's also the preservation of those beta cells. Even if you say, ok, well, the person got 2 or 3 extra years of not having type 1 diabetes, well, when they did get it, what were those first few years like? Maybe they were a lot easier. Maybe they were able to be managed on initially a long, or just a little bit, a tiny bit of insulin. They weren't having these wide fluctuations in glucose levels. If we've improved their quality of life for several years, that is something.

: I agree with you wholeheartedly. I also loved her discussion around adding other drugs. This is not going to be the 1 and only drug that is ever going to be used to delay the onset of all kinds of autoimmune diseases. They're looking at Crohn disease, they're looking at, other groups are looking, other companies are looking, right? And that's important too. Is there going to be where we say, you have these 3 antibodies, but you don't have this one. Can we make that person a cocktail in the future to delay the onset longer, to prevent, what if you could get to 10 years? Would you do that? Those are the discussions in the future that we can have.

Diana Isaacs, PharmD, BCPS, BCACP, BC-ADM, CDCES

: Yes, it's definitely very exciting. Well, thank you for this very rich and informative discussion, and thanks to our audience for tuning in. If you enjoyed the content, please subscribe to our e-newsletters to receive upcoming MedCast® episodes and other great content in your inbox.

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Drs Diana Isaacs and Natalie Bellini discuss the everyday challenges of managing type 1 diabetes and underscore the need for new treatments to improve the quality of life for people living with type 1 diabetes

Challenges in Managing Type 1 Diabetes and Pressing Need for New Therapies

There's starting to be a lot of efforts to screen people with TrialNet. I'm curious your thoughts. Once someone has those autoantibodies, I know in the trial a glucose tolerance test was done. What do you think about maybe using CGM [continuous glucose monitoring] to identify that stage 2 versus doing a glucose tolerance test?

 There's some great data out of the Barbara Davis Center that CGM metrics can be helpful to identify people who are high risk of screening. The only issues with CGM are it's dependent on what people eat, is one issue. It's less standardized than the oral glucose tolerance test. It seems like the data can be variable. They can be more variable than with the OGTT data. It's something that's appealing and as we're thinking about rolling screening out to more and more people in the population, we're going to have to be more flexible about the things that are going to work for different people and how to identify different people because at the end of the day, the more people that are getting monitoring, maybe it's not the kind of gold standard perfect monitoring but if it can be applied to more people, that's the thing that's the most important. We're going to be thinking a lot more about maybe glucose tolerance tests aren't going to work for you but what are the other things that we know can give us good information that might be useful? Maybe even hemoglobin A1C screening for some people too because it's just one finger stick even though it's maybe not quite as sensitive as that oral glucose tolerance test. Maybe if someone has in their hemoglobin A1C, it could give you a lot of information.

That's a good point. That would be a lot easier, a lot more convenient to do.

Maybe in the beginning what you do is you put a sensor on the patient and say, look at these spikes. Now we need to do an official test because it's part of the FDA approval. Even for the finger stick, we've had families who have called and said, we think our son has Type 1. I'm like, well, go give him some pancakes and syrup and check his blood sugar and call me back. That same idea is, are you seeing the spike or not? Then we can put you into this protocol.

 It's going to be interesting, these next steps now that we have something to intervene. We need to be talking about ways to identify more and more people that are going to benefit because depending on where you live, a lot of the screening that's available is only to family members. Hopefully, more and more general population screening is going to become available. Another big need monitoring guidelines for these people who we know are at risk, who are antibody positive because there's different things out there, but I think it would be nice to have clear guidance, especially for family practitioners and primary care providers who are going to be seeing these patients a lot and need to have a plan for what to do with them.

As a person who practices endocrinology, these aren't my patients yet. They're going to be if they're positive but they're not yet. How do I get the pediatrician, the primary care, the family practice groups to screen for these so that the patient is identified as quickly as possible and we really can move forward?

 There's a big need for education now because a lot of people aren't familiar with the idea of stages of diabetes but kind of clear guidelines for monitoring. It's a no-brainer for people who are family members in the United States because they can get screened for free through TrialNet but if it's someone who doesn't have a family history, then it's more complicated. There are some states that have screening programs that are available and then JDRF has a link on their website to screening that people can pay for or do through insurance but some of the kinks need to be ironed out of that.

A lot of people that get Type 1 diabetes, don't even have a family history so it's kind of like, well, who should be screened? Anyone with any type of autoimmune disorder in their family. There's a lot of questions.

 There's been some talk about potentially including genetic screening for high genetic risk for Type 1 diabetes on the newborn screen. Then people who would be really high risk then could get followed up over time with autoantibodies. It's very interesting. That would be a big paradigm shift on the newborn screen. It's not diagnosing something; it's just diagnosing a high genetic risk for something. There's many, many logistics that need to go into place, but I think, potentially really, exciting and opportunities to intervene early in disease and change that kind of natural trajectory for a lot of people.

Well, thank you so much for sharing all your knowledge and wisdom with us. We really enjoyed talking with you today and having you here.

 No problem. This was fun, you guys. Thanks for inviting me. I appreciate it.

Expert healthcare practitioners discuss the potential of CGM and other technology to identify signs of type 1 diabetes.

Potential of CGM and other Technology to Screen for Type 1 Diabetes

The study that the FDA indication was based on was a prevention study. It was people who didn't have what we classically consider as clinical diabetes yet. They met criteria for stage 2 diabetes. These were relatives of people with type 1 diabetes. They were 8 to 45 years of age, and they were stage 2. They already had at least 2 of those islet autoantibodies, and they were already having changes in their blood sugars on an oral glucose tolerance test. You have them drink the glucola, and then you're starting to seeing changes in blood sugars, but not yet meeting those diabetes criteria. These are people who we know are at super, super high risk of progression to clinical diabetes, kind of like right on the edge of getting diabetes. And then they were followed over time after that kind of one-time 14-day course of drug with these oral glucose tolerance tests. They did them 3 months after drug and then 6 months, and then every 6 months over time to catch diabetes early and see if there was any difference in the rates of diabetes development in the people who got placebo or drug.

Would you be able to share some of the key findings from that trial? How did teplizumab group compare with placebo in terms of that type 1 diabetes progression?

In the first study that got published in the 

, I think in 2019 they were able to see that treatment with drug was associated with about a 2 year delay in progression of diabetes compared to people who got placebo. And then we did a follow up study a couple of years later that was looking at how people's beta cells made insulin in response to drug versus placebo, and followed people up for longer. And we saw that the effect of drug on the progression of diabetes lasted closer to 3 years. It was 32 and a half months compared to placebo, which was super exciting. And then the other thing that was really, neat is, when you look at the way that people's beta cells make insulin before and after they get the drug. If you follow these people over time before they got treatment, their amount of insulin that they're making is decreasing, decreasing, decreasing. These are kind of right on the edge of getting diabetes, and they're about to go over the cliff. But then- and that continued to be the case for people in the placebo group. But in the people who got drug, you see this cool reversal where they start to increase their insulin production at three months and then at 6 months where they looked significantly different from the placebo group. Not only was diabetes delayed, but it seems like people's beta cells were working better early on after they got this drug pretty quickly.

It is. Speaking of that, I was actually just curious, because I know there's also the ongoing PROTECT study, which is being done in people with already diagnosed type one diabetes to protect their beta cells. And I believe the protocol for that is a 12-day infusion. I'm just curious if the rationale, if you can share why this one was 14 days, but that one is being done with 12 days?

I think it's just about convenience for patients. Everyone's super excited about the possibility of these kinds of therapies, but then there's what are the logistics of getting this out to people. And a 14-day infusion means 2 weekends that have to be covered and figuring out weekend coverage for people. And wouldn't it be great if you could get the same effect with a 12 day infusion. And that's the idea, with putting it down to 12 is- probably it has the same benefit, and if it could help patients and be a lot easier for patients to get the drug, then it would be great. And then the PROTECT study, the idea with that study is that in people who have stage 3 diabetes, I think is testing kids. And they're testing 2 doses of the drug kind of right after people get diagnosed and at 6 months with the idea that the prevention study was just one course. Maybe if you could give people a second dose, you could prolong the effect with drug. And the goal would be to preserve people's C-peptide in production. For people who don't study diabetes, C-peptide is the way that we measure someone's endogenous insulin production for people who are taking insulin or getting treated with insulin. And the idea here is that we know that people who have type one diabetes who are still making some of their own C-peptide, long term do much better. It's much easier to manage their diabetes. They usually require less insulin with less low blood sugars. And then in terms of diabetes complications, they also do a lot better over time. That would be the goal with treating right at diagnosis.

I have a good question. Of all the studies you've done, what's the longest? We talk about this 24 months or 32 month, what's the longest? Because some people that we've talked to as clinicians have said, it's only 2 years. How long can it be? And again, this is all brand new. And I think people need to understand that this is just the first step, but I would love to know more about how long you have prolonged. And what is the role then of this zinc, the anti-zinc co-transporter antibody versus any other ones? That's a two-part question.

First question is what's the drug that's had the longest effect on delaying diabetes. This is the only drug that's ever been shown to successfully delay diabetes. Which is the drug, first drug that's had the longest effect. Two things. First of all, this drug we know has an almost 3 year delay on the timing to having diabetes. Which if you think about, particularly for a little kid who's high risk of progressing to diabetes. If you think about 3 years and someone who has a child and not having to take insulin, man, that's like maybe getting through a formative period. Maybe getting through adolescence, where that could make a big difference in your quality of life. And it's going to be an individual decision, but it's something that could impact people and their quality of life. And that said, though, you really hit the nail on the head when you said this is kind of just the first step. There's the possibility of repeated dosing when people start decreasing their own insulin production again. And then most of the people who are in this area, that we're going to have to do some kind of combination therapy long term. The next steps are going to be using other kinds of agents that target other kinds of mechanisms, that maybe could be used in addition to teplizumab. That we could kind of attack this from multiple angles and have longer duration of effects, and ultimately maybe even a cure. But we can find combinations that prolong the need for insulin for a longer period. That was the first part. And then the second part was about different kinds of autoantibodies, and if that makes a difference. We know that depending on which autoantibody you present with, that can be reflective of different kind of phenotypes of type 1 diabetes. And people are recognizing more and more that type 1 diabetes is probably a heterogeneous disease with different people presenting different ways. For example, we know that age, at the time that you present, the age that you present with type 1 diabetes can be associated with different phenotypes. Where people who present as little kids have a much more severe disease course. They progress more rapidly; they lose their own insulin production more quickly. Versus people who present as adults when things kind of seem to move a lot more slowly. And there have been some studies that have shown differences in which autoantibody kind of presents first and which ones you have, and how that may be associated with differences in the way that you present with disease. And the kind of holy grail is we can kind of identify these kinds of differences, including which autoantibodies are positive, and kind of be able to understand what kind of treatments would work the best for different people who have those different phenotypes. We can provide a more precision approach and give the best treatment for each individual person. But for now, the numbers are stillsmall and we're still so early. Those are the steps down the line that we need to cross later.

That's interesting. I know while 2 or almost 3 years was the median, obviously some people were shorter or longer. I'm curious, what was the longest? How long did it delay in some people for type 1 diabetes?

It's hard to answer that question because you always want to compare people to placebo. Because even though we were kind of selecting everybody at stage 2, there's probably individual features that make one person not as likely to get diabetes as rapidly than another person. But the last time we followed up the data, there were some people who had gotten drug that it had been over 5 years and they still hadn't progressed to diabetes. And I know that Kevin Herald, who's the person who has been the person who's spearheaded teplizumab in type 1, is planning on looking at people who were kind of long-term responders to teplizumab. And seeing if he can understand some of the kind of individual features that predicts the best response in those individuals.

I truly love the idea of then saying, you're a long responder and maybe this is the only drug you need, but you're a short responder and now let's put these 2 together. You might get teplizumab and something else 6 months later. Or you might need teplizumab every 6 months for years, but if you never develop full blown type 1, haven't we done something in the right direction? That's the goal, you mentioned young children. What if I can get that young child through college? Most of them would raise their hand and say, infuse me every 6 months. I've got 12 days or however many days it turns into.

You know what, maybe a lot of people think it may end up that there's some kind of regimen and then involves an abduction kind of therapy that's something like teplizumab or antithyroglobulin where you have this kind of big hammer that kind of depletes T-cells and then they recover but then you have a maintenance therapy as well that's kind of a less big gun that you could take for longer with kind of less immunomodulation so that it could be a long-term treatment. I totally agree. Even if you must start insulin, maybe if really low doses or just basal or something like that, it still would make a big difference in quality of life and be moving that needle forward.

The question a lot of people have is, well, what are the adverse effects? How well tolerated is teplizumab? We know it's the infusion. Are the adverse effects just during the infusion or are there some that are kind of lingering later? Can you share some of that?

 Yes. In the PREVENTION study, it was well tolerated. As we mentioned, the logistics of kind of getting a 14-day infusion are kind of annoying. That's one thing. Then you have this drop in your T-cells that recovers kind of over that next month or so and so you must be careful and make sure you're being careful in terms of infectious exposures, but people tolerate the drug really well. The biggest adverse effect in this study was that a lot of people get a rash that usually gets treated with Benadryl® but can be itchy. That's the main issue that people had but otherwise, it was well tolerated and there were no kind of serious safety issues in the study.

That's amazing. It really is amazing because usually, we start with tell us the adverse effects and it's 10 minutes of discussion. There really aren't. Patients do. They tolerate it very, very well.

I'm curious. We talked a little bit, we brushed up a little on the PROTECT study, but what's next for this drug? I imagine we're not stopping here. What is next for teplizumab? Even if you could share some top-line results from PROTECT or if there's other future studies that are planned as well.

 I don't have results yet from PROTECT but one thing is extending the indication potentially to the new onset population, looking at efficacy there. Another thing that is extending the age groups that it's eligible for. The FDA indication was based on the PREVENTION study, which started at age eight, was the lowest age. We know kind of as we mentioned, little kids who are presenting, could benefit from a 3-year delay in their diabetes diagnosis and are the ones who are often progressing the most frequently and are the ones we're kind of hearing about the most. I think prevention is really interested in extending the indication and doing more testing. TrialNet who is the international trial group that put on the initial PREVENTION study is looking at doing a trial on little kids to look at efficacy of the drug in stage 2. The other thing everyone's thinking about is combination regimens. What's going to be a great combination to put with this drug to improve that duration of effect? I'm not aware of a combination trial that has started yet, but there is lots of talk about what those could look like. I'm a big beta cell person, I think it would be cool to try something like verapamil or a drug that targets beta cell health in combination with teplizumab and see if that makes the effect last for longer.

Dr Emily Sims reviews the study design of the clinical trials with teplizumab and shares key findings from the completed phase 2 trial.

Study Design and Key Findings from Teplizumab Clinical Trials in Type 1 Diabetes

Hello, and thank you for joining this MEDcast

 series titled “Applying the Latest Evidence to Delay the Onset of Type 1 Diabetes.” I am Diana Isaacs, an endocrine clinical pharmacy specialist and the continuous glucose monitoring program coordinator at the Cleveland Clinic Diabetes Center in Cleveland, Ohio.

And I am Natalie Bellini, a nurse practitioner specializing in diabetes management with the R&B Medical Group in Williamsville, New York. Today, we'll discuss the latest clinical evidence on new and emerging treatments that can delay the onset of Type 1 diabetes.

We are joined by Dr Emily Sims, a pediatric endocrinologist at Riley Hospital for Children and a physician scientist in the Indiana University Center for Diabetes and Metabolic Diseases and the Herman B. Wells Center for Pediatric Research. We are so excited to have Dr Sims here who was an integral part in the Teplizumab clinical trials. To begin with, can you describe for us the stages of type one diabetes and discuss why interventions that delay the clinical progression of type one diabetes are so important?

 The stages of type one diabetes start officially once someone has multiple islet autoantibodies that test positive. Once you have at least 2 positive islet autoantibodies, at that point, we know that your lifetime risk of developing type one diabetes approaches 100%. And we would call someone stage 1 type 1 diabetes once they've developed multiple islet autoantibodies. Once you reach the threshold of starting to have changes in your blood sugar, but you don't yet reach the American Diabetes Association criteria for diagnosing diabetes, that's a person who would say has stage 2 type 1 diabetes. You start to have changes in your beta cell function and your glycemia, but kind of not yet reaching those clinical criteria that would be stage 2 diabetes. And then now we consider stage 3 diabetes as someone who used to say had new onset diabetes. Having that A1C of greater than 6.5%, having an oral glucose tolerance test, 2-hour glucose value of greater than 200 or fasting blood sugar greater than 126. And then clinical symptoms of diabetes, we would call stage three diabetes.

Let's talk about type 2 diabetes so our listeners and our viewers can understand. What happens first? The interesting part about diagnosing diabetes is we look at fasting blood sugars, but can you talk about why that might not be ideal?

In type 1 diabetes, fasting blood sugars are probably one of the later things to change as you progress along that spectrum to stage 3 disease. We know that when your beta cells and your pancreas make insulin, there's 2 phases of that insulin production in response to sugar or some kind of meal exposure. There's this big surge that you get and then a later phase of insulin secretion. In type 1 diabetes, early on that first phase of insulin secretion is the thing that changes. And those kind of stimulated time points of that insulin secretion are what we see differences in early on. And then it takes a long time to see changes in the fasting blood sugar. Early on you're going to see changes in early insulin secretion and maybe later time points or intermediate time points of an oral glucose tolerance test when you're testing somebody for diabetes. And that kind of testing at earlier phases can help you identify people early when there's an opportunity to intervene, and make a bigger difference than if you wait until you see changes in that fasting number.

Thanks for explaining that. That was a good explanation. I know you've been involved with the clinical trial with teplizumab, which has now been FDA approved to delay the onset of type one diabetes. Kudos to you and your team for all that amazing work. Can you tell us how it works? What is its mechanism of action?

It is exciting. This is a huge, huge step, landmark step for people who've been working on therapies that target underlying pathophysiology of disease in type one diabetes. This drug is a monoclonal antibody to CD3, which is a protein that's on the surface of T-cells. And what this drug does is in the trial that the drug- the FDA approval is based on, you give a 14-day infusion of this drug and it causes a temporary depletion of people's T-cells. And then as those T-cells recover, hopefully less of the kind of bad T-cells that attack your pancreatic beta cells increase. And then the people who respond the most to this drug seem to have an increase in, they call them partially exhausted CD8 T-cells. And so again, those are the type of T-cells that kill your beta cells that make insulin. And they're less autoreactive and they're less likely to be reactive against those beta cells. And you have less beta cell killing.

What a great response. That is perfect.You're almost calming down that T-cell activation. You're almost saying stop doing what you shouldn't be doing in the first place?

Yes, exactly. And another important thing to think about is that, for this treatment it was a one-time course of this drug. Andpeople had temporary depletion, but then things go back to normal. And they still had this long effect of the drug, even though it was only a one-time treatment with the drug.

Dr Emily Sims provides an overview of the stages of type 1 diabetes (T1D) and explains how teplizumab slows the immune-mediated destruction of beta cells.

Emily Sims, MD

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