Robin S. Goland, MD

 Before we close, now that we have this exciting tool, what will each of you be doing in your own center for your patients and for your group to screen patients and get this tool on board, assuming it is paid for, which is a very big assumption, and assuming you’ll have the capability to have a 14-day infusion somewhere. Who will you be screening, and how will you spread the word among your colleagues within your own groups? Dr Goland, why don’t we start? We’ll go around, then you, Dr Simmons, and Dr Quattrin, so I can learn and steal the best-case scenario from each of you.

 I’m waiting for more information about the rollout. Patients and family members who specifically want the drug will do the antibody screening commercially. We are going to come up with our plan, which will involve some element of home care, I hope, because I think that would be the easiest for the patients. It’s difficult to get around in New York, but we’re working out the details.

 Dr Simmons, anything different that you’d be doing?

 As we’ve talked about, people with a family history are at highest risk. Those are the people who we definitely have always tried hard to get screened. The messaging now when you say the same thing is a lot more interesting with something being available. I’m hoping that the same messaging we’ve been giving about getting our relatives screened will result in more screening happening through TrialNet, for example. We also have the opportunity to do general population screening in Colorado. We’re working with a lot of pediatric education health networks through our system to get the word out to let people know they can be screened. The autoimmunity for children study can screen remotely now too, so we’re working with places that don’t have the opportunity to screen or even a great laboratory option for commercial antibodies, where we can help do screening remotely. I’m also helping to lead a project called Ask the Experts, where if somebody tests positive for antibodies in an area that’s more rural and doesn’t have support, we try to work with a local provider to train them on how to support that patient, and then in the meantime can provide remote care.

That is kind of a big picture of how we’re going to do screening. Hopefully, in lots of people and supporting lots of people. As far as administering teplizumab, there are many details to work out, but I have the privilege of being involved in starting an early type 1 diabetes clinic at our center. So we’re hoping to be able to administer the medication at our center once we work out all of the logistics.

 Dr Quattrin, anything different you’ll be doing?

 Informing all health care professionals that this is available is important, and making it easy for them to order these antibodies, telling them, this lab, this code, make it easy so they don’t have to spend a lot of time. In terms of a systemic and sustainable approach, there is a need for lobbying. In New York state, and Dr Goland knows, we screen for conditions that are far rarer than T1D [type 1 diabetes]. The difference and impact in addressing and preventing, or diagnosing early, may not be as relevant in terms of cost-benefit. I think we need to also lobby, and from my standpoint until I can do something like that, I’m going try to connect with Kimberly’s group and any other group to try to test as many people as possible.

As far as the practical implications, the pediatrician is the captain of the ship, so the family will talk with them. They always do when we’re proposing a trial, and we often talk with them ourselves. When you hear even the remote possibility of cytokine release syndrome, there is an uneasiness. It’s important that the data that are available regarding the timing of when these adverse effects occur, which is usually earlier, not only the incidence but the timing and the severity, is widely explained and available because it makes a difference when you might be able to do 3 injections at the site and the rest of the infusion possibly at home. I don’t know that right now my colleagues and I would feel comfortable with the treatment being done at home. There are tons of details to be worked out in terms of being able to administer the new medicine.

 What I plan on doing in my own site, I work with 15 adult endocrinologists. First, I have a call tomorrow with the chief of medicine to say, if there’s any interest, we could be an infusion site. I know we don’t know the logistics yet, will it be initiated in the office, as you said, and then the rest at home, or some kind of hybrid model of that? But to do a mass mailing like the way I would normally solicit patients for clinical trials, we could leverage our electronic records. I could identify everyone in the practice with type 1 diabetes and have an appropriately crafted letter talking about the antibodies. Of course, they’d have to check to see if the antibody levels are covered, and where they can get them free or for a reasonable price commercially available. But I wouldn’t send that letter until we have the tool to do something about it, not just to inform them about it. Either they’ll go to a pediatric endocrinologist if it’s positive for the rest of the work-up, to their adult endocrinologist, or a referral or something like that to do this bigger time, to be able to do that. It’s such an exciting tool for all of us, and you’ve all made me more enthusiastic for what’s on the horizon.

I’d like to thank all of you for this rich and informative discussion. Before we conclude, I’d like to get any final thoughts from each of you on what key message you would give to your colleagues. We’ll start with you, Dr Goland.

 This is a very exciting time for people with type 1 diabetes and their relatives. On the horizon are opportunities for delay and eventually prevention and cure of type 1 diabetes. Stay tuned.

 I would say the door has now opened, which is extremely exciting, and I look forward to seeing what comes through the door in the future. I think everyone should feel very excited and hopeful, and not overwhelmed, because it can be very overwhelming. There’s so much information. There are great resources out there to support anyone who is interested in screening, or potentially administering a medication, or interested in a clinical trial. The Juvenile Diabetes Research Foundation has a page on how to get screened. TrialNet, of course, has information on how to get screened. The Autoimmunity Screening for Kids program has information on screening. You have at least 3 great resources to reach out to, to get support.

 I echo what Drs Goland and Simmons said. It seems almost like a dream for those of us who have been involved in this field for such a long time. People with type 1 diabetes deserve this and they deserve more. There’s so much innovation that if we can delay the onset, they may be able to take advantage of those innovations and new therapies. It’s important that we are not in a silo as subspecialists, but rather we collaborate with all the health care professionals. As I mentioned, I know TrialNet can mail a kit, and there are other efforts that make things possible for families to look at this and look at the future as a brighter future.

 Well, thank you. I’ve learned a great deal from each of you. If our audience even learns a fraction of what I’ve learned, it’s very successful. Thanks for watching this 

on “The Future of Type 1 Diabetes Management.” If you enjoyed the content, please subscribe to the e-newsletters to receive upcoming peer exchanges and other great content in your inbox. The material contained in this document is the property of Intellisphere LLC and should be considered confidential for internal purposes. Thank you very much for joining us.

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Drs Robert Busch, Robin S. Goland, Kimberly Simmons, and Teresa Quattrin discuss strategies to facilitate screening of type 1 diabetes and improve management of disease.

Strategies to Improve Screening and Diagnosis of T1D

 Our patients with type 1 diabetes have many other health issues as well. Dr Simmons, you’re a celiac expert, how does that impact your patients who have type 1 diabetes and some of the other factors they have?

 I don’t think I’m a celiac expert more than anybody else; I think we all to some degree are celiac experts because celiac disease is so common in our patients with type 1 diabetes. The data show about 6%. When we’ve looked in our clinic data, we have almost 8% of our children with type 1 diabetes who have celiac disease. It is a condition that often requires a lot of comanagement. If you ask any patient who has both type 1 diabetes and celiac disease, which disease is harder to manage, I have heard every single patient tell me celiac disease, which is always insightful because it tells you what an impact diet can have on someone’s everyday life. Many of our patients, even though they likely have celiac autoimmunity before they’re diagnosed, most are not diagnosed with celiac disease until after they develop type 1 diabetes. We have a collaborative approach with our GI [gastrointestinal] colleagues that is great, where we try to manage type 1 diabetes and the diagnosis and adjustment period first before they jump into managing an entirely new disease. The other thing we always must remember is that celiac disease can make diabetes management really complicated if they’re not absorbing their food well, for example, with unexplained hypoglycemia and variable insulin dosing day to day. There are many factors to consider, and I think collaborative care is always the best way to approach that if it’s available.

 If I could jump in, I think in the 30 years I‘ve been at this, my adult patients are increasingly incredibly healthy. I tell my young trainees that when a 70- or 80-year-old patient with type 1 diabetes comes to the office, puts their arm around my shoulder and calls me sweetheart, this is a visit where no one’s going to do one thing I suggest. But I think that’s fine. I completely agree with Kimberly; a patient I diagnosed with celiac recently, 6 months later, she came back to the office and asked if I could give her type 1 diabetes a second time. Anything would be better than that celiac diagnosis. It was so touching and such a unique perspective, but like what you’re hearing with the children, changing what people eat and that level of vigilance is very difficult and tricky.

 As adult endocrinologists, we’re managing cardiovascular risk protection. Where’s your ACE [angiotensin-converting enzyme] or ARB [angiotensin receptor blocker]? Also aggressive statin management, and beyond statin management, looking for underlying heart disease. There’s a lot of other impactful things as well.

 The good news is type 1 diabetes is a disease of 1 problem, the blood sugar. Because I’ve been nagging them for 30 years, these are usually people who exercise and eat a lot of kale. Compared to my people with type 2, they are living healthy and playing tennis, and whatever this pickleball situation is; someday when we cure this, I will learn to play it. They are very healthy. My experience, at least in New York is that—and this is borne out by many of the studies in the older type 1s in the exchange—the patients are doing remarkably well and living complication free. That doesn’t mean it’s easy because the obstacles and burden are remarkable.

 Since you mentioned celiac, I should tell you the first patient I will start on the drug if it is dysglycemia, is like the father I presented about at grand rounds when I was a fellow many years ago. He had primary hypothyroidism, Addison disease, vitiligo, B12 deficiency, and type 1 diabetes. He has never had DKA [diabetic ketoacidosis] since, has managed himself, and is one of my healthiest patients, with 5 endocrine problems. I show him off to every student who comes in. He’s now in his 50s; I met him for short stature when he had hypothyroidism when I was a fellow. He married someone he met at a diabetes meeting, and she has celiac disease and type 1 diabetes. They have 3 kids. The child I treat has Hashimoto disease, and even though I’m not a pediatric endocrinologist, he has 4 out of 4 antibodies positive. He didn’t want to drive to Boston to be in the TrialNet trial, but knowing the drug is approved, that was my first phone call I made to them. So they can‘t wait. As you said, you talk to someone who has a family member with diabetes, and they all want in. The patients I’ve called so far, they all want their kids to be screened uniformly, there’s no question about it. If it prevented diabetes, you said for a year, but if it prevented it for a month, they would be happy with that.

We are often screening our thin patients with type 2 diabetes when they come in for latent autoimmune diabetes and find it, especially if they have any other autoimmune process like vitiligo, or B12 deficiency, or anything else. If we look, we find it.

 I think most specialists who are listening to this would know, but for anybody who’s more of a general practitioner, many families assume that the environmental trigger is the flu virus or whatever virus happened immediately before they presented to clinical care. In that respect, those families might think, “It wouldn’t have helped if I had been screened and detected earlier because I didn’t know I was going to get the flu.” It’s really important families realize that that process and being able to detect it has been going on for months to years, and that particular virus is not the initial environmental trigger. It’s what happened at the end that made them sick enough to show up in somebody’s office.

Experts in endocrinology share their approach to managing type 1 diabetes along with related health conditions.

Managing T1D Comorbidities

 Several of you mentioned that there might be other therapies on the horizon, so even though you’re delaying things 2 to 3 years, there might be something else that comes along. Dr Quattrin, would you like to review some of the other studies with some other novel medications that may be on the horizon?

 It is important while we are focusing on the recent approval that we realize there are also other potential drugs, and they have been used with some success. We talked briefly before about abatacept, there has been a prospective, well-run study with this drug. It prevents T-lymphocyte activation. This drug, for example, at 24 and 36 months, showed that the endogenous insulin measured by the gold standard, which is a C-peptide, was higher in participants. And because this was successful, there is an ongoing study in stage 1 of diabetes. Alefacept is another fusion protein that binds CD4 that also has had promising results. All of these have different variations as to whether they affect the insulin immune surge or hypoglycemia, but ultimately, when I say that they had positive results, I’m alluding to endogenous insulin production.

The other drug that has been published about is a drug that works on B cells because they also contribute directly and indirectly to the autoimmune process. This is rituximab, which is an anti-CD20 antibody, and that also had positive results. At the beginning, Dr Goland mentioned ATG [anti-thymocyte globulin], which has several actions, depleting D cells, and affecting the dendritic cells, which are important in your immune process. That also was a successful study. Now, it’s important to realize that some of these medicines, as pointed out by Dr Simmons, require more premedication and they may have more adverse effects. The other trials I want to bring up, even though this drug is not in development, is the anti-TNF [tumor necrosis factor] agents. After a very successful study, it’s not in development, but that may be an option.

One important thing about the abatacept is that all these studies have what we call responders and nonresponders. Abatacept was also a study where using an algorithm with artificial intelligence, there was this ability to detect who was and wasn’t a responder. Of course, if you take 100 of us adult and pediatric endocrinologists and see if we all agree on who is a responder, how to judge a responder, should it be the insulin-adjusted glycated hemoglobin, should it be the time in range, there is not agreement. But to what Drs Goland and Simmons have nicely outlined, as we move forward, we should be able to collect data so that we make more educated decisions on behalf of patients who are at a high risk of type 1 diabetes.

A lot has been talked about recently regarding the study taking place using a plasmid vector that is designed to transfer DNA into the cells. This is an ongoing study, and it would then alter the process leading to our immunity. There are several ongoing studies that have potential. Unfortunately, studies with subcutaneous insulin or oral insulin, that we hoped would work, ultimately did not meet the end points. I think we base, rightly so, a lot of our tenets on animal models. But when you talk with beta cell physiologists, they eloquently describe the difference, and that’s why we can’t always expect to replicate those trials.

 Will these studies allow people in who have already had teplizumab who haven’t yet developed diabetes to see if you could extend the time when they don’t get diabetes, or does that exclude them from the other studies?

 Typically, patients are naive patients, but I cannot comment as to what might happen with the design of a study. I cannot talk as much about the European system, but the FDA is looking more favorably at adaptive designs. We may be able to do studies where, naturally we see if an individual responds, and if an individual doesn’t respond, then you would stop. One more thing I want to say, the study that led to teplizumab approval was done with 1 infusion, but we don’t have data to say what if we did another infusion. My point is that in rheumatoid arthritis, in Crohn disease, patients have courses of immunomodulators. They are not always kept on chronically, and sometimes the dosing changes based on the response. Frankly, I don’t see why this couldn’t potentially happen for people at high risk for developing stage 2 and stage 3 type 1 diabetes. It should be almost a continuum of the spectrum.

 Dr Simmons, what do you think will be the future of this, given that some of our colleagues will start using it and then it will start snowballing? Do you think it will be the standard of care, that patients who have the 2 antibodies, who have dysglycemia—assuming it’s affordable and can be given more widely at centers—do you think this will be incorporated, just like how pumps or CGMs [continuous glucose monitors] have exploded in the past decade? What do you think will happen down the line with this tool?

 I think it will become the standard of care, hopefully. There is a large transition period to see how that all plays out. But I think if you look at other fields like oncology, for example, where they didn’t have anything, and now they have treatment and these adaptive designs in how they treat patients, I think the future is looking more like that, where there may be repeated drugs, different drugs, and a better ability to predict who will respond and who won’t. Clinical trials as we just discussed will probably have to be designed differently in order to be successfully enrolled. We want to continue doing research because this drug is opening the door, but we want to have other options that are the most beneficial for everybody out there who’s going to develop type 1 diabetes.

 It sounds like in pediatric endocrinology it will be like adult endocrinology, where 30 years ago we had nothing. We had sulfonylurea, but we didn’t have any statins, we didn’t have any good blood pressure drugs. We had NPH [neutral protamine Hagedorn] in regular and double void urines. Compare that to what we have now; it makes practice a lot more fun. I think you’ll be experiencing the same thing in your field as well. You’ve had pumps and sensors, but to have this and the other potential immunomodulators—none of us will ever retire, it’s too much fun to practice. What else is coming out? What about beta cell regeneration and other tools like stem cell transplantation? Dr Goland, if you’d like to take that on.

 I’m also never going to retire because I think we might see cell-based therapies for our patients. It’s quite exciting that we’re in a collaborative project where we’re doing skin biopsies, and our colleagues can generate stem cell-derived beta cells that make insulin in the dish. I think that in the next 10 years, we might see the ability to transplant those cells. It’s quite exciting, and like I said earlier, the more options for our patients and their families, the better. We’ve come a long way from NPH…and rightfully so.

Teresa Quattrin, MD, reviews emerging clinical trial data on novel therapies to delay the progression of type 1 diabetes.

Investigational Therapies for the Management of T1D

 When the patient gets the 2-week infusion done, they haven’t had the adverse effect, and they go home, who should be monitoring the patient afterward, and what kind of monitoring, Dr Simmons, would you recommend for those patients who’ve had the infusion? Now they have gone home from the infusion site, and they’re happy they will delay their diabetes, so what kind of monitoring would you recommend?

 This is another area where we have limited evidence to know what to do. It’s important to know that some of these patients will develop type 1 diabetes, and so you don’t want them to never be seen again. Having some sort of monitoring to make sure they’re not progressing to clinical diabetes probably every 6 months or so would be important, and then having a tool at home, a way to check blood glucose levels, so if there’s any concern they can seek attention earlier, would be a good way to start.

 Would you send a letter to their pediatrician saying this is what they’re doing? Or do you think the person administering the drug, the site administering would be doing the monitoring? What would you recommend for that to be done?

 To be honest, in talking with many of my general pediatric colleagues, they would feel more comfortable with that follow-up being done in a pediatric endocrinologist’s office. Not that they can’t do it, but their systems are very burdened, and it’s hard to assume additional risk and knowledge about something they don’t already know. I see the follow-up probably being in a pediatric endocrinologist’s office for the time being.

 Dr Goland, since you treat adults and you’ll be heading off type 1 diabetes in the adult with relatives, will you be doing the follow-up in your own practice, or your colleagues? Or will you have the primary care clinician do that?

 We follow our antibody-positive TrialNet patients, and many of them ask for a clinical appointment because they’re aware that they are high risk. I would do exactly as Kimberly said, and I agree that our internal medicine colleagues are very overburdened, and there’s no way that they would be able to take this on. So if we order this infusion, they then are antibody-positive patients who have received teplizumab, and they’re ours. I would follow up with them every 6 months. I don’t think I would prescribe a sensor, but a home glucose monitor, which I almost never use, and I would give them instructions about when to use it and when to call us, because you’d hate for somebody in that group to go into DKA [diabetic ketoacidosis].

 I plan the same as you. To me, I’m looking at it as like when we treat prediabetes off-label with medication, we’re the one doing it. The primary care doctor is uncomfortable even with prediabetes if we initiated the treatment.

 The other thing that is important is that the pediatrician, primary care physician, or health care provider is aware that there is that risk because it would be helpful. We’re trying to have patients have an emergency card they keep in their wallet, so if they see their primary care provider, an ED [emergency department] physician, or an urgent care physician, they have the card that says they’re at risk for type 1 diabetes, so that makes it onto the differential diagnosis for whatever’s going on.

 People are so overburdened, it’s very hard to communicate.

 Dr Goland, in terms of who’s administering the treatment, I would imagine it would be our colleagues, whether it’s an adult endocrinologist or a pediatric endocrinologist, unless it’s a provider who has type 1 diabetes themselves and is very comfortable managing diabetes. I think this will be our bailiwick, unless any of you think otherwise, that it would be outside of the pediatric endocrinologist or the adult endocrinologist practice?

 I don’t. It’s incumbent upon us to be good communicators, both with the public and with health care professionals. I personally do not see this happening, and it shouldn’t because that’s all we do, so presumably we’re aware of potential issues that can arise.

 One other thing I did not talk about during the adverse effect profile, because as we mentioned earlier, most people tolerate this medication extremely well, but there still is a risk of cytokine release syndrome. It’s not as high because of how the drug’s been modified and how the dose is ramped up at the beginning, but it is still a potential adverse effect. It must be given in a safe environment, especially to start, so that we have good outcomes as we’re entering into this new phase of administering immunotherapies.

Kimberly Simmons, MD, MPH/MSPH, leads a discussion on long-term monitoring for patients with type 1 diabetes and which providers are most likely to administer and manage teplizumab treatment.

Robin S. Goland, MD

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