Schafer Boeder, MD

Schafer Boeder, MD: Role of SGLT2 Inhibitors and GLP-1s in Type 1 Diabetes

22nd Annual World Congress Insulin Resistance Diabetes & Cardiovascular Disease (WCIRDC)

, Schafer Boeder, MD, an endocrinologist and assistant professor of medicine at the University of California, San Diego, delved into the use of adjunctive therapies, including sodium-glucose co-transporter 2 (SGLT2) inhibitors and glucogon-like peptide-1 (GLP-1) receptor agonists in 

, insulin resistance, and cardiovascular risk.

While T1D has traditionally been associated with lean individuals, Boeder highlighted the growing prevalence of obesity in this population and the need for treatments beyond insulin monotherapy to tackle these metabolic challenges. Despite promising data extrapolated from type 2 diabetes (T2D) studies, he indicated these therapies lack robust, type 1-specific outcome data, particularly regarding kidney and cardiovascular protection.

The discussion also underscored the barriers to broader adoption of SGLT2 inhibitors, particularly the risk of diabetic ketoacidosis (DKA). Boeder emphasized strategies to mitigate DKA risk, including careful patient selection, education on risk management, and the use of protocols such as STOP and STITCH. He also pointed to the potential of emerging technologies like continuous ketone monitoring to further enhance safety.

Looking ahead, Boeder advocated for more research focused on T1D, such as the ongoing Sugar and Salt trial exploring renal outcomes with SGLT1/2 inhibitors. He also highlighted the transformative potential of advances in obesity medicine, including newer GLP-1 receptor agonists and triple agonists, which offer substantial weight loss and broad metabolic benefits. These developments could signal a shift toward more holistic and preventive care approaches, even as challenges such as cost, side effects, and regulatory approval remain.

Disclosures: Relevant disclosures for Boeder include Cecelia Health, Dexcom, Eli Lilly, REMD, and Biotherapeutics Inc.

Boeder S. The Role and Safety of SGLT2i and GLP1 RA Therapy in T1D. Presented at the 22nd Annual World Congress Insulin Resistance Diabetes & Cardiovascular Disease (WCIRDC). Los Angeles, California. December 12-14, 2024.

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Schafer Boeder, MD describes the potential role and safety of adjunctive therapy, including SGLT2 inhibitors and GLP-1 agonists, for patients with T1D.

 What can we do with our patients to bridge the gap until we have a more solid cure? I think I can start off, and then Linda can jump in, or anybody. Are these hybrid closed-loop systems? We have 4 different ones on the market. I think you all would agree with automatic insulin delivery, modulating basal rate, alerts, and alarms that you could set individually that, for adults with type 1, my clinic has gotten so boring. Patients come in, their [hemoglobin A1C (HbA1C)] is good, time below range is really low, glycemic variability—and it’s not like you slapped [it] on, they have perfect control. You do some adjustments, a patient gets engaged in their care.

 We are still struggling on the pediatric side with some of the closed-loop technologies. We have some families that plug it in, go chug, and then we’re just tweaking little things, but kids’ insulin continues to change throughout childhood because of adolescent behaviors that lead to that. We had that nice type 1 diabetes exchange graph with peak [HbA1C] in there with 9.2%, same as before [the] DCCT [trial] across the population. So at least in our clinics, I’m still having kids [on Control-IQs walk in with HbA1Cs] of 10. And then, I got to go back, and it’s usually bolus, bolus, bolus, but don’t bolus after you’ve eaten because the system has already given you insulin; that’s why you’re going low. Avoiding the next bolus is not going to help you here. On the flip side, when we can manage them or when they manage well themselves—having just come off diabetes camp earlier this month, I have never seen so many blood sugars of 120, 130 in the morning. Still, the days are a little bit unpredictable. I don’t think we did much ketone testing at all in the morning. I’ve been doing camp for 25 years. It never looked that way before.

 I was up more of the night with the alerts and alarms from the CGMs [continuous glucose monitors] with the staff trying to figure out what to do with them. I think it’s [promising], and access is important. We know that underrepresented populations are still much less likely to be using those devices. We’re doing well in kids right now with CGM incorporation across our clinics, but we need people to be insured, [and for] the underinsured to get them and to have access. As pediatric endocrinologists, getting that stuff down to the little kids is also going to be important, and there have been huge advances there.

 I’m going to take that as your final point. Egils, do you want to end our program with some final thoughts?

 Well, we just celebrated the centenary of the discovery of insulin. I have a [Toronto, Ontario, Canada] newspaper that says, “Diabetes cured” that I show my patients; so, 101 years later and even though overnights are great with AID [automatic insulin delivery], insulin is still a pretty poor hormone replacement. I look forward to the day that we’re using teplizumab to prevent progression of diabetes.

 Well said. I think you emphasized, Linda, that although we do have these hybrid closed-loop, automatic insulin delivery systems, we have a long way to go, even for people who have access to them. Justin, my good friend, any final thoughts before we end the program officially?

 I just feel so fortunate to get to work in a field where we can have these discussions. About just a few years ago, we [had] been trying immunotherapy right and left. We’ve been doing antigen therapy right and left and disappointment after disappointment. Now we’re talking about how to implement immunotherapy in the way that we treat type 1 diabetes. I think of it as we’re at the dawn of the immunotherapy era. As endocrinologists, we don’t usually use immunotherapy drugs, unlike some of our other subspecialist colleagues. It’s an exciting era, but we’ve talked a lot about some of the challenges that we’re just starting to get our arms around as we enter that era. I look forward to getting to do it with people like you.

 Well, thank you for that. Very exciting time as well. Schafer, you get the final word on that.

 Well, I would just say I learned a lot today. Thank you for all that expert knowledge, that was fantastic. I’m going to echo a little bit what was just said to some degree that it does feel sort of a dawn of a new era. Thank God for insulin, but it has been limited, and despite all these great technologies and CGM and closed-loop, the picture is not quite as rosy as Steve painted it in his clinic, where everything’s great. We see people come into the hospital, wearing their pump, but they’re in full-blown DKA [diabetic ketoacidosis]. There are a lot of problems still that we haven’t been able to solve even with great insulin therapies, new and faster insulins, and longer-acting insulins. There are still issues with increased cardiovascular disease, with the majority of patients not meeting glycemic goals, and issues with DKA. There’s a lot of work to do, but it’s such an exciting time to have some therapies, that we’re not just trying to play catch-up and treat by giving more insulin and figuring out different ways to use insulin, but to actually be able to get ahead of the curve a little bit is just very exciting and optimistic.

 Well, thank you, Schafer, Linda, Justin, and Egils, I learned a lot myself. It’s been a pleasure working with all of you, and I wanted to thank everyone for viewing and watching this 

program. Don’t forget, they have an e-newsletter, where you can look at prior programs and future programs on different topics. Thank you very much for watching.

Expert endocrinologists provide final thoughts on addressing unmet needs and improving the management of T1D.

Bridging the Gap for T1D Management

 Schafer, take us beyond stage 2. We got prevention, preservation once you already have T1D [type 1 diabetes], and replacement. I know Schafer was involved in islet cell encapsulated therapies, so talk a little bit about that. It’s the future, nothing approved at the current time, but I think it’s important to mention it.

 It’s interesting. I’m not going to use the C word, cure, because I think everyone has a different sort of definition of what that might mean, and I’m not sure that these qualify, but when we look at these different sorts of categories of prevention, progression, and replacement, I think, interestingly, replacement is the farthest down the road, in a sense. It’s always that one that seems right around the corner, and yet it’s been difficult to give effective replacement. So there has been progress, and there are exciting studies and trials that are going on. A lot of them, as you alluded to, relate to giving islet cells back. That can be done via infusion. They can be, for example, infused into the portal circulation, where they sort of spread out and end up in the liver, and they have their action there. They can be encapsulated and then surgically implanted under the skin. So there are different approaches to those, and they’ve all shown different degrees of promise. In some cases, even effective beta cells have lived there and made insulin. What we haven’t seen is that consistently across many patients, where we’re getting people consistently off insulin or making meaningful changes to their insulin regimen and their glycemic control. The other side of that that’s an ongoing concern is the need for immunotherapy, immunosuppression therapy. It comes with its own issues and concerns and baggage. You’re exchanging one chronic disease for another, in a sense. You’re going to be on these immunosuppressive therapies. There are still big hurdles, but it remains an exciting space and one where progress continues to be made.

 To think 5 years ago, you would have had nothing to say. Look at all the different things that folks are working on. I know, Egils, you might have some comments on the cell replacement.

 Well, starting with islets, the biggest problem is supply. Thousands of organ donors wouldn’t be enough to cover all our type 1s, and, of course, the need for immunosuppression. Pluripotent stem cells is the answer, and we’ve got a treatment now that potentially has no limit as far as availability of those cells. Did you guys see the human trial, the documentary?

It’s about 2 patients in early trials—spoiler alert, it didn’t work for them—but the epilogue, there’s a slide showing that in 2022, last year, a patient receiving stem cell therapy, on immunosuppressants though, [had] 99% time in range, no insulin. [Brian] Shelton, I think, his name was.

, everything. It’s really interesting. The next step is to obviate the use or the need for immunosuppressants, whether by encapsulation or by changing the cell around.

Schafer Boeder, MD, and Egils K. Bogdanovics, MD, share approaches to prevention, preservation, and replacement therapies for the treatment of T1D.

Investigational Approaches for Treating T1D

 As endocrinologists, what’s our role in pediatric or adult diabetes in making and getting teplizumab accessible for families? It’s like anything that you don’t have insurance for: it’s quite expensive. Do you have any ideas along those lines? We don’t work for the company, but there are programs. The company that owns teplizumab hired a third party to help with reimbursement, and there are financial assistance programs. Does anybody have anything to add to that?

 Yes, it’s called the COMPASS Navigator program.

 My experience has been that they’re helpful. But a limited number of centers are able to do this logistically. What we don’t want to happen is a patient isn’t able to get this drug with benefit if they don’t live close to 1 of these big centers. It’s a big undertaking because you’re talking about not a single day but 14 days away from work…. I don’t think we have this figured out. Pediatric oncologists have a better sense of this because they commonly do this. This is why there’s Ronald McDonald House and these kinds of things. This is something we need to think about right now. This ties into the PROTECT study. So far, we’re talking about stage II. Relatively speaking, it’s a small number of patients. It’s not beyond the pale to think that this is going into stage III soon. Then you’re talking about an immensely greater number of patients doing 12 days of immunotherapy.

 Or into stage I. As we start to do screening earlier and understand when the optimal time to intervene is, I don’t think we can say that we definitively know. This may be a widened window, potentially in both directions.

 It has been estimated that there are 300,000 individuals at risk for developing stage 3 in the United States, but they’re hard to screen for. They don’t have any symptoms. But if this or any other therapy gets approved for stage III, it’s going to be like wildfire because as soon as a parent has a child, what do they want to do? What could they do? It’s good that we have a buffer zone to set up these infusion centers.

 We’re figuring out how to do this from a structural standpoint. A lot of smart individuals working are on it, but there’s a long way to go in terms of how to logistically put this infusion in place for patients, whether it’s at home or in infusion centers. The onus is shared. We all have to do that work. But if you’re a provider who takes care of patients with type 1 diabetes, and you’re expecting in the future that a patient—or a loved 1 of a patient—will walk into your clinic and be screened as an appropriate candidate for this therapy, there’s a finite window to deploy the therapy. Thinking about how these logistics will work in your own site sooner rather than later is probably worthwhile because it’s a big process. Finding the technical expertise, the individuals to do the infusion, and the monitoring takes a lot of time. Get started on that process. If you’re thinking, “I’m going to use this therapy,” then try to reach out for the resources available.

 You referenced that not everybody responded to the therapy. There were certain HLAs, antibodies, and timing. As we rush short immunomodulatory therapies, we’re going to see that it’s appropriate—given that we have a therapy that looks like it’s highly effective and can do a job in some patients—to keep the door open for other sequential therapies and combination therapies because we’re talking about a delay. We’re not talking about a cure of diabetes. I love the phrasing that we need cures, not a single cure, for type 1 diabetes. There’s still going to be a need to innovate, still going to be a need for other treatments. When we think about treating type 1 diabetes, you alluded to stage I. What works in stages I may not work in stage II and III, and the treatment that works for 1 patient may not work for another. Even for an individual, the disease evolves over time and the treatment needs to be tailored. You would never take somebody with cancer and put them on 1 drug, say good luck, and move forward. You’d be monitoring, and that’s something else we need to get better at: monitoring biomarkers’ response over time. If you fail 1 drug, you’d try a different thing. That evolution needs to happen here. I’m not sure how we do that effectively, but it’s something we need to consider in this space.

 This shows how complicated it is. Having teplizumab available and approved opens the door for other therapies. It’s hard to do these type 1 studies. It takes time, especially screening for stage II and the different combinations. A lot of individuals have said, “Why don’t you give teplizumab once a year?” Studies are underway. This is a good segue. What other therapies out there to delay the progression of type 1? Justin, you go first. Linda, you’re involved in TrialNet, so you can add on.

 To frame the studies that are out there, I think of 3 categories. First, we think about antigen therapy. You mentioned the DVT [deep-vein thrombosis] study, where we tried to use insulin as an oral antigen. To this point, in antigen therapy, I haven’t seen great progress, but that’s the area where they’re thinking about different ways of delivering antigen. The idea is that by delivering antigen, you’d bring about a tolerance for that antigen. The second category is immunotherapies. We’ve talked about teplizumab a lot, but other immunotherapies have garnered attention. Abatacept comes to mind. It’s another immunomodulatory agent that influences the way T-lymphocytes stimulate one another. A recent abatacept study came out in which it was initiated in stage I. There was some hope that it would prolong and bolster C-peptide production. It didn’t do as well as I had hoped it would.

The thought becomes, what if you combine these therapies? I put that into a third category. The idea that a single immunomodulatory agent working on 1 antigen is going to bring about long-lasting tolerances doesn’t make sense. Could there be synergistic relationships? As Linda was talking about, what happens if you give a second dose of this? Conceptually, it makes sense to combine things like abatacept with teplizumab to promote longer-lasting immune tolerance. That’s what we’re going to see in the future. Now that we have teplizumab, trials will be teplizumab plus placebo vs teplizumab vs something else. We’ll start to see how we can improve on this first drug that’s on the market.

 There’s 1 big challenge we’re going to encounter there, but I’m not 100% sure. We’ve referenced the 14 days or 12 days of infusions, and they need to take off work. It’s not that we didn’t identify more patients who were eligible in [TrialNet] TN10. Some patients chose not to do it because they were worried about the drug. They didn’t know if it would be effective. It was a placebo-controlled trial. Some patients couldn’t take the time off or didn’t want to.

Another issue we’re going to hit in these comparator trials is what if patients don’t want teplizumab? Will there need to be teplizumab plus placebo, teplizumab plus drug, and then a drug-only arm to accommodate that? I’m not sure. That complicates the trial design even further because you need patients opting to go into 1 group or the other. We’re going to need good statisticians and trial designers to help us.

 It’s hard for me to fathom that someone would say, “I don’t want my child to get it or my first-degree relative because I have to work.” It emphasizes the point that we have to help our patients who are candidates for it to have accessibility.

 I laugh in part because there was 1 patient in Indiana who was potentially interested. He had a young family at home, and he was keen to come. But his family was like, “You can’t be gone for 14 days. There’s too much going on.”

 It was a huge issue. It was hard because you have a limited window to get the drug—you have to be not yet stage III and not reverted to stage I.

Experts in endocrinology share challenges of patient access to type 1 diabetes treatment as well as resources to combat these challenges.

Schafer Boeder, MD

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