Cori Cross, MD (Host): Welcome to PedsCast, a podcast brought to you by Children's Hospital of Alabama in Birmingham. I'm your host, Dr. Cori Cross. Thank you for joining us today. We are joined by Dr. Giovanna Beauchamp and Dr. Ortal Resnick from the Endocrinology Department at Children's of Alabama and the University of Alabama at Birmingham.

We are going to have an interesting discussion on glucagon-like peptide-1 receptor agonists, which is quite a mouthful, better known as GLP-1 receptor agonists. Dr. Beauchamp and Dr. Resnick will be assessing GLP-1 receptor agonists' potential effectiveness for patients with type 1 diabetes. Thank you for joining us.

Ortal Resnick, MD: Thank you for having us.

Giovanna Beauchamp, MD: Thank you very much for having us. We appreciate it.

Host: Of course. So in discussing type 1 diabetes, maintaining glycemic control is obviously paramount to good care. Dr. Beauchamp, how challenging is it for patients with type 1 diabetes to maintain glycemic control with the currently available treatments?

Giovanna Beauchamp, MD: Unfortunately, it is pretty difficult to achieve good diabetes control with current treatments. We do want to say, thankfully, for the last a hundred years, we've had insulin. Insulin is the gold standard. It's the mainstay therapy for type 1 diabetes. And we've also had, of course, so many advances in terms of technology with insulin pumps, with continuous glucose monitors, with automated insulin delivery systems. Yet, despite all of this, we are still achieving good control per all of the standards in about 20% of our patients. So, that still means that about 80% of our patients are actually not achieving good glycemic control with current standards, and this is why it's time to add something else.

Host: That's a large percentage. Now, in addition to glycemic control, which is a challenge, weight and obesity can also be a challenge for some patients with type 1 diabetes. Dr. Resnick, can you explain those issues and how much of a concern weight gain is in these patients?

Ortal Resnick, MD: So actually, weight gain is a big issue with type 1 diabetes. It was thought that type 1 diabetics are lean and tend to lose weight. But actually, we know now that obesity is a big issue, and about 60% of the population with type 1 are suffering from overweight and obesity. And we know that insulin by itself is an anabolic hormone that causes weight gain. And on average, a patient that starts on insulin treatment gains five kilograms in the first five years of treatment. So, we know that the treatment by itself causes weight gain. It's like this vicious cycle that you keep gaining more weight. And as we gain weight, we have more insulin resistance, so we need more insulin. And again, we know now, we understand that type 1 diabetes go in correlation with obesity. And we also understand that obesity by itself increases the inflammation, increases the beta cell destruction, that beta cell needs to deal with more. And so, they end up having more severe diabetes earlier in their course.

Host: So, obesity is something obviously that we want to avoid. It's basically one of those things that isn't just a problem. It's a problem down the line, because it causes the disease to progress faster.

Giovanna Beauchamp, MD: And it also makes it difficult or harder to treat. Absolutely.

Host: Got it. Right. Because you end up chasing your tail with needing more and more insulin. So, can you explain the role of GLP-1 receptor agonists in patients with type 1 diabetes and/or obesity?

Ortal Resnick, MD: So, GLP-1 is a hormone secreted in our body, helping us control our insulin sensitivity and help us feel more full after we eat. And so, by giving it as a treatment as a receptor agonist, it's helping us to increase this effect. And so, we know it's very efficient with obesity and with type 2 diabetes because, again, it helps our glycemic control and it helps also to lose weight. And this effect is exactly what we want in type 1 diabetes. We want as well that the insulin that we give will work better. And also, as we just discussed, we want the weight loss because, you know, obesity by itself is crucial in the management and the prognosis of type 1 diabetes. This treatment, we think, are going to be very helpful in managing type 1 diabetes.

Host: Now, can I ask you just a question about GLP-1s in general? So, they work by both what you said, making the insulin more effective, but they also work by curbing your appetite. How in type 1 diabetes-- because as you discussed before, they need to eat on a regular basis to maintain that glycemic index. How do you sort of reconcile those two things?

Giovanna Beauchamp, MD: When GLP-1s are used in type 1 diabetes, they still help curb appetite, right? Which is, again, from central mechanisms in your brain. And the good thing is you end up eating less, fewer calories, which then leads to weight loss. As you lose weight, your insulin requirements then are also lower, right? As you eat more and you gain weight, then you have more adiposity. This increases insulin resistance, which then makes you gain more weight, which then makes you need more insulin, which then increases more insulin resistance, which is going back to that feedback loop that Dr. Resnick was talking about. And so, in type 1 diabetes, if we can hit it centrally, open your brain with curbing that appetite, then we end up eating less and needing less insulin, which then we know has good benefits in our hearts and in our kidneys, so on and so forth.

Host: You're able to switch their path from one where it's obesity-driven to one where you're actually able to control their appetite, decrease the obesity, and therefore get the disease in better control, which will have less effects down the line of kidneys, eyes, all the other issues that we have with diabetes.

Giovanna Beauchamp, MD: Right.

Ortal Resnick, MD: On top of that, we don't need to eat regularly to control the diabetes. We just need to make our sugar stable. It is important, and it's a good note to mention that when we are decreasing the appetite, we need to make sure that our nutrition will be balanced and will be good because, very easily, you can become malnourished if you decrease your appetite and you eat only non-nutritional food. So, it's a great point and it's a good point for everyone. Everyone who's on GLP-1 treatment, we always need to make sure that they're eating balanced meals and they have all their nutrition values. And type 1 diabetes is not exceptional to that. It doesn't mean that when you have type 1, you have to eat in a scheduled routine. We do ask our patient to do it, just because it makes the insulin injection be easier to monitor because you need a dose before you eat. So, it's better when you have a routine, so you're able to control it. But it's not necessary that you have to eat more food to control your diabetes.

Host: That makes sense. And that's a great segue into what I'd like to talk about next, which is the safety and the side effect profile, which is what you're touching on, the fact that you need to continue to have a well-planned and well-balanced diet because you're eating less. That applies to everybody whether you have type 1 diabetes or not. The fact that GLP-1s are naturally occurring hormones in our body means that we're putting something in that our body is actually already used to. So that all being said, what do you see as the most typical side effects of patients who are using this? Are there any adverse effects that anyone should be concerned about? Could you discuss that a little bit?

Ortal Resnick, MD: The most common side effect that we see with GLP-1 use in all the groups is nausea and vomiting. And that is because the GLP-1 slows down our gastric emptying. And people that are used to eating big portions with the slow gastric emptying will cause them nausea and vomiting. So, the best way to manage it is to eat smaller portions and to decrease the fat in them, and that helps with this side effect. Another thing is increasing the dose of the GLP-1 gradually and slower really help to fight against this side effect.

And another thing that has been reported in research as side effect is decreased appetite, but that is actually our goal. So, I don't see it as a side effect as much. That is part of what we are going to get from the treatment. When we are thinking about type 1 diabetes, the reason that we are more questioning the treatment is because there was a concern about hypoglycemia and about hyperglycemia, because we are decreasing the insulin, how will it affect glucose balance.

So, about hyperglycemia, the literature shows that it's not increasing. It actually has less hyperglycemia and less DKA, diabetic ketoacidosis event. So in that sense, I feel pretty comfortable with my patients. For the hypoglycemia, because the insulin works better, and we are losing weight and we need less insulin, we are prone for hypoglycemia. So, the way to manage it-- and again, we just need to be aware of that, that it can cause hypoglycemia and we need to treat with less insulin. And to find this fine balance of how much insulin do we need and not to cause hyperglycemia, this is something that this is why we are seeing our endocrinologist when we are doing it. And this is why we are monitoring and this is why we are checking. And we will decrease the insulin initially and decrease it as needed to prevent this hypoglycemia.

Host: Now, these are medications that people are on basically most of the time for the rest of their lives. Now, patients with diabetes are used to that already because they're going to have to be taking insulin for the rest of their lives. So, this is just a lifestyle situation that they have to deal with, because the beta cells in their pancreas aren't working correctly. So, we have to give them things to fix this.

That being said, I've read that there are concerns or there are theoretical concerns with being on like a GLP-1 for the rest of your life. Does that play a role at all in type 1 diabetes and the treatment?

Giovanna Beauchamp, MD: I don't know that we have all the long-term data yet to necessarily be able to comment on that. It is very likely that these are going to be lifelong treatments just because we will see the benefit in obesity and in decreasing complications more so than the benefits in A1c and the time and range. We will see all of the benefits. But whether our patients are going to have to be on medicine lifelong or not, I think it may be too early to comment on that. Dr. Resnick may have another comment.

Ortal Resnick, MD: Just to add to that, we have been using GLP-1 for type 2 diabetes for about 20 years now. To know about long-term, like lifelong information, we just don't have this data. Like, there is not enough time to see. From what we know from the last 20 years is that it's pretty safe. There is also dose change. There is the dose that you use to lose weight, and then there is like the maintenance dose that a lot of times we are decreasing the dose to keep the same weight because we don't want to lose more weight. And so, there are also a lot of questions that we need more time to know.

Giovanna Beauchamp, MD: We need more time. And we need more research, right? Because we are now extrapolating data. And it's difficult to compare these studies and we should not, right? Because we are comparing different populations, different study sizes. We are not necessarily comparing things that are easier or harder to compare, but we can only extrapolate from what we have in type 2 studies and obesity studies and in type 1 studies with small sample sizes. And so, we are extrapolating all of the safety that we can from that.

Host: Right. And that segues into really what you have been doing. So, you wrote a mini review about GLP-1 receptor agonists in patients with type 1 diabetes. But again, the N is small because there isn't a lot of research that is being done and you really had to extrapolate data. How did you go about assessing the effectiveness of GLP-1 receptor agonists in these patients? And what did your mini review sort of show?

Ortal Resnick, MD: We did a literature review looking at both retrospective and randomized clinical trials. And we analyzed our data mostly from the randomized control trials, understanding that when we are comparing it to placebo, we're getting a more reliable information. You are right that there is not a lot of literature. And also, most of the literature that has been done was done on an old GLP-1, which was a daily GLP-1. We know now that we have a better weekly, stronger medication that works better for type 2 diabetes. And we are expecting them to work also better for type 1 diabetes. But we analyzed around 12 articles that have been done on type 1 diabetes. Some of them are small with like just 18 patients, but some are with 1400. So, there are some big researches that's been done on type 1 diabetes. And then, we analyzed what are the results, how it affected the A1c, the weight.

They also looked a little bit at the C-peptide, which shows us the beta cell effect. There is assumption that with early start of the GLP-1, we may help with a better cell load and help to preserve some better cell function. But again, all of that is needed to be researched and you need to catch the patient very early in the disease so that, again, a lot of future direction and we cannot make assumptions based on these studies. But definitely, like we mentioned, it helps a lot with weight loss, improve A1c. The A1c is improving, but it's only in around 0.3%, which all patients with type 1 diabetes will tell you, "This is my difference between my different visits." It doesn't necessarily mean a lot, but the fact that they're losing weight and their total daily insulin is decreased, this is a big outcome that we think will affect their long-term complications. And again, to be able to look at the microvascular risk, we need to longer research, which we don't have yet.

Host: Right. I mean, to your point, what we're really trying to deal with isn't just the change in hypoglycemia or the blood glycemic control during the day. But also, these patients, because as a pediatrician, I think of what happens to them down the line. We're thinking about their eyes, their kidneys. These are all organs that we want to preserve with their vasculature for as long as possible. So, anything you can do to preserve that is huge, even if you're not seeing the change in the A1c.

Giovanna Beauchamp, MD: Absolutely. And if I can make a quick comment on that, the best way that we are going to see improvement in those potential complications is by decreasing the amount of insulin that our patients will need, right? Because again, a lot of insulin around increases adiposity. And then, this is what directly causes all of these complications in our hearts, in our kidneys. And so, through this decrease in our total daily dose of insulin, that's how we're going to achieve a lot of success.

Host: So, last question really is-- these treatments, they seem to-- I think you've explained how they'd benefit patients with type 1 diabetes going forward both in the terms of glycemic control and weight management. Despite the studies being small, I am assuming that it's being used off-label or it's being used more than it's being even researched in these patients because they have the comorbidities of type 1 diabetes and obesity. Can you speak to that a little bit?

Giovanna Beauchamp, MD: Absolutely. Definitely, we are seeing the rise in the use of GLP-1s in type 1 diabetes. And a lot of it, as you very well said, is off-label. I think that when we all believe in the benefit of GLP-1s in diabetes in general and in our patients who have type 1 diabetes and also live with obesity, we definitely see absolutely the benefits there. We know that there has been an increase in its use from the last five years until now. The rise has been significant among pediatricians and among endocrinologists for sure.

Host: In summary, can you give us a 30-second take-home message for our listeners? Dr. Resnick, do you want to go first?

Ortal Resnick, MD: Sure. Thank you. I think my take-home message is obesity is a big issue in type 1 diabetes. We need to change our set of mind that only type 2 diabetes correlates with obesity. And we need to find good treatment for weight loss, better glycemic control, as we are doing very good with the treatment we have now, but not good enough. Twenty percent from our population getting time and range is just not enough.

Host: Dr. Beauchamp, is there something you wish that other endocrinologists knew to make them feel more comfortable in using this type of treatment with their patients?

Giovanna Beauchamp, MD: I wish that we all felt a little bit more comfortable using GLP-1 therapy in type 1 diabetes, because I do think that those of us who have used it off-label or for the use of obesity, we see wonderful benefits in our patients. And I think they are all very pleased with those results, which then leads to better diabetes control, and then overall better outlook in life and in being able to live a healthy and happy life.

I think that there are very great ways and we don't have algorithms, like you need to follow this specifically for every patient. Of course, we want to individualize care. But there are very great ways of doing this and doing it safely for patients without causing a lot of hypoglycemia or ketosis or any of the other potential problems.

Host: Well, thank you both for joining us today. This has been a very thought-provoking discussion. I know I've learned a lot. I'm sure our listeners have too. For more information or to refer your patients to Children's Alabama, please visit childrensal.org. That's childrensal.org. That concludes this episode of Children's of Alabama PedsCast.

If you found this podcast helpful, please share it on your social channels and be sure to check out the entire podcast library for other topics that might be of interest to you. Please remember to subscribe, rate, and review this podcast. Thanks for listening to this episode of PedsCast. I'm your host, Dr. Cori Cross.