Stages of Type 1 Diabetes and Mechanism of Action of Teplizumab

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

Natalie Bellini, DNP, FNP-BC: 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.

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

Emily Sims, MD: 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.

Natalie Bellini, DNP, FNP-BC: 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?

Emily Sims, MD: 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.

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

Emily Sims, MD: 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.

Natalie Bellini, DNP, FNP-BC: 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?

Emily Sims, MD: 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.

Transcript Edited for Clarity