Mental Health Hospitalizations in Adolescents; Stem Cell Therapy for Type 1 Diabetes

TTHealthWatch is a weekly podcast from Texas Tech. In it, Elizabeth Tracey, director of electronic media for Johns Hopkins Medicine in Baltimore, and Rick Lange, MD, president of the Texas Tech University Health Sciences Center in El Paso, look at the top medical stories of the week.

This week’s topics include an oral GLP-1 agonist, activating two satiety pathways, mental health in U.S. adolescents, and stem cell transplants for type 1 diabetes.

Program notes:

0:40 Stem cells for type 1 diabetes

1:40 None had hypoglycemia afterwards

2:40 Autologous stem cells?

3:20 Oral GLP-1 agonist

4:20 Primary endpoint hemoglobin A1c reduction

5:20 Weight loss modest

6:20 Injectable GLP-1 plus an amylin analogue

7:20 Both those with diabetes and those without

8:20 No increased safety events

8:40 Mental health hospitalizations in adolescents

9:40 Kids’ Inpatient Database (KID)

10:40 Females accounting for increase

11:40 67% of hospitalizations

12:57 End

Transcript:

Elizabeth: An oral GLP-1 receptor agonist.

Rick: Stem cell therapy for type 1 diabetes.

Elizabeth: What’s the state of mental health for our kids in the U.S.?

Rick: And can two obesity medicines coadministered be better than one?

Elizabeth: That’s what we’re talking about this week on TTHealthWatch, your weekly look at the medical headlines from Texas Tech University Health Sciences Center in El Paso. I’m Elizabeth Tracey, a Baltimore-based medical journalist.

Rick: And I’m Rick Lange, president of Texas Tech University Health Sciences Center in El Paso where I’m also dean of the Paul L. Foster School of Medicine.

Elizabeth: And we are spending a disproportionate amount of time in NEJM [New England Journal of Medicine] this week. Why don’t we turn first to the one that I think is just really fascinating? Might we have a cure for type 1 diabetes?

Rick: Type 1 diabetes usually manifests during early childhood. It’s usually a result of an autoimmune reaction where something in the body stimulates it to attack the pancreatic cells that make insulin, what are called the beta cells. As a result, these individuals need to be on insulin lifelong. If we could somehow regenerate pancreatic cells, beta cells, that actually worked.

There’s a company that took a pluripotent stem cell and differentiated them to become pancreatic beta cells. They injected these into the portal vein — that is the vein that feeds the liver — to see first of all would they engraft and secondly could they make insulin. Could they do it in a way that could actually regulate things?

This is a phase I and phase II study, 14 individuals. In most of these individuals, they did a single injection and then monitored them over the course of a year. They could detect insulin being made. None of these individuals had hypoglycemia afterwards. Most importantly, 83% of them were able to get off insulin altogether. The two that weren’t able to get off of it, it decreased substantially their dose. They wanted to get the hemoglobin A1c below 7 and it happened in all individuals. They wanted glucose to remain within the normal range 70% of the time — that’s the goal — and they were able to do that as well. Terrific news. Now, the flip side is these patients have to be on some sort of immunosuppressive therapy. Really encouraging studies.

Elizabeth: Very encouraging. I’m wondering about the potential for harvesting stem cells from people with type 1 diabetes and enabling this whole process to take place with their own stem cells, thereby avoiding the need for immunosuppression.

Rick: That may be the best way to do is autogenic, is to take your own cells and do that. It takes a fair amount of work and what you’d like to be able to do is have these where you can take them off the shelf. Currently, it would be very difficult, expensive, and not quite standardized.

Elizabeth: I get that, but my guess is that that’s probably where this is headed, since we’re seeing so much personalized medicine and I specifically cite cancer therapies relative to that. Let’s also consider this issue of these pancreatic beta cells being resident in the liver. I find that to be quite fascinating. Is there a specific place where they take up residence?

Rick: This particular study did not assess that nor the number. I can tell you that the number of cells that they actually injected into the humans provided insulin levels that were both adequate to maintain a normal glucose they were able to autoregulate.

Elizabeth: Remaining in the New England Journal of Medicine then, let’s turn to this one where I said, wow, an oral GLP-1 receptor agonist. And this one we were discussing before we started to record — these tongue-twisting names that these people come up with for all these drugs. This one orforglipron, that’s how I’m going to say it. I’m sure somebody else says it differently than that. It’s a small molecule, non-peptide, GLP-1 receptor agonist. As we know, the vast majority of these meds so far have been injectables.

So this is a phase III trial where they evaluated three doses of this medicine or placebo once daily for 40 weeks. They had them all start and then they titrated the dose up to the highest dose over this 40-week period. They had 559 participants who underwent randomization with their mean hemoglobin A1c of 8%.

All three doses of this medicine were superior to placebo with regard to their primary endpoint, which was a reduction in the hemoglobin A1c to a space that would be actually OK. That mean hemoglobin A1c at week 40 was 6.5% to 6.7% with orforglipron. They also had a mean change in body weight of 4.5% with the 3-mg dose, 5.8% with the 12[-mg dose], and 7.6% with the 36-mg dose, 1.7% as the comparator with the placebo.

Their most common adverse events, mild to moderate gastrointestinal [GI] events, most of which were occurring during that dose-escalation period. Once it was stabilized, it got OK. They had a permanent discontinuation, actually, among all of their participants. But among those who got the drug, 4.4% to 7.8%. So this is looking pretty good and it avoids the injection.

Rick: Yeah. The weight loss was relatively modest compared to the injectable. Now, it’s different patient populations, so unless we have direct comparisons, it’ll be difficult to say. It also had other beneficial effects that lowered lipids. It lowered blood pressure. It looked like the weight was continuing to go down and it hadn’t plateaued at 40 weeks. So maybe to continue it longer may have more beneficial effects. We’re going to need some head-to-head comparisons.

Elizabeth: I agree. They note in here that the oral bioavailability is up to 40% of this med, so that’s a good thing, and the prandial state does not impact on one’s ability to take it whenever you feel like doing that, also benefits over the subcutaneous injection route.

Rick: Now we have another oral agent, semaglutide [Rybelsus], but you have to time it. You can’t eat it with a certain amount of food; you have to drink a certain amount of water. It’s a little bit more tedious. What we’re doing is we’re developing oral medication, we continue to get better in terms of the bioavailability, so that will continue to improve.

Elizabeth: I, for one, really welcome the emergence of these because I think anything that has to be injected is probably not optimal.

Rick: Yeah. Speaking of injectable medication, let’s go to the injectable GLP-1 semaglutide [Ozempic, Wegovy] and it does two things. One is it increases insulin secretion, decreased glucagon, but more importantly it acts in the brain to decrease somebody’s desire to eat.

Well, there’s another agent that acts in a different hormone, but also in brain receptors as well. This satiety hormone is called amylin and is also involved in the central regulation of food intake and body weight and glycemia, and there is a long-acting amylin analogue called cagrilintide that also has been shown to reduce weight. But it does it by a different mechanism than the semaglutide. It’s also injectable. So the real question is, OK, will the addition of both of these, because they work through different mechanisms, be better than either one alone?

There are two studies, one done in diabetics that are overweight, and the other one is done in overweight people that don’t have diabetes. They administered these together, started a low dose, and over the course of 16 weeks increased the dose to maximum, and then tried to maintain that over the course of a year. And they followed weight loss, hemoglobin A1c, and they also followed the side effects.

Compared to placebo, there was a significant weight loss. It decreased weight by about 20%. For those that had obesity and diabetes, it decreased weight by about 14%. And for those with diabetes, it decreased hemoglobin A1c. They were more likely to be in the normal range and they were more likely to have lost either 5%, 10%, 15%, or 20% of their weight compared to placebo.

The side effects are very similar. Most individuals experience some GI side effects, some nausea, constipation. That was usually in the phase where they were increasing the dose and they were able to maintain maximum dose in about 60% of individuals. But even those that couldn’t tolerate the maximal dose, they still experienced a significant increase in weight loss and normalization of their hemoglobin A1c.

Elizabeth: It makes a lot of sense to me because we know that both the feeding behavior and satiety pathways are pretty complicated, so utilizing more than one way to skin that cat seems to make a lot of sense to me.

Rick: Yeah. And do you get additional benefit? No increased safety, adverse events. This will be an evolving story.

Elizabeth: I just have to say, and as for me, I think prevention is worth all of these put together.

Rick: Yeah.

Elizabeth: Finally then, let’s turn to JAMA and this is a research letter taking a look at something that I think is pretty concerning. These are sex-based differences in pediatric mental health hospitalizations at U.S. acute care hospitals. We’ve reported many times that this is largely adolescents who are being looked at in this particular analysis. We have a tremendous number of mental health issues that are taking place in that population and we saw a rather dramatic increase in that with, I would say, two factors: the prominence of social media and the pandemic.

This research letter starts out with the statistic that about one in five U.S. children have a mental health diagnosis. When they look at pediatric mental health hospitalizations at acute care hospitals, they increased almost 26% between 2009 and 2019. However, nobody has really looked at this thing post-pandemic and so that’s what they saw. They were looking at the number of pediatric mental health and suicide self-harm related hospitalizations in 2022, and then they characterized the sex-based differences among that group.

They used a database called the Kids’ Inpatient Database (KID), which is released every 3 years by the Agency for Healthcare Research and Quality and that, of course, compromises things right away because it’s only every 3 years. But even so, given all the data that they have here, what they found is it’s about 60% of these hospitalizations occur among female youth.

In 2022, there were an estimated just shy of 200,000 mental health hospitalizations, a decrease from 2019 and the first observed decline during this study period. However, the number of suicide and self-harm-related hospitalizations increased each study year, reaching a maximum in this 2022 data set. For the female youth, this is where this increase is really accounted for, while males were experiencing a good deal less of this. It clearly points to a need to figure out what is it that’s impacting female youth that’s giving rise to suicidality as well as some of these other mental health issues.

They do note also that both for males and females depressive disorders were the most common principal diagnoses. And the authors admit that the compromise of their data set is that they didn’t look at psychiatric long-term or rehabilitation hospitals. They also excluded emergency department visits, so they couldn’t account for boarding in emergency departments that took place without hospital admission.

Rick: Yeah. Elizabeth, on the one hand you celebrate the news that the total number of pediatric mental health hospitalizations declined between 2019 and 2020. That’s the first time that’s happened since 2009. The female hospitalization rate has increased substantially, so then in 2022 they comprised about 67% of the mental health hospitalizations and 71% of those related to suicide or self-harm. Targeting this particular group and finding out what has changed.

Elizabeth: I agree, and there’s, of course, nothing about this that would help to point to that I mean… and I think it’s tempting, at least for me, to turn right to social media, and what we even reported very recently about how girls respond to that and everything that takes place on social media. The boys are gaming and they don’t have the impact of the bullying that we’ve reported that is seen elsewhere.

Rick: Yeah. If you compare females to males, the females have a greater susceptibility to these stressors related to family dysfunction, to peer relationships, and to social media that you mentioned. As you said, how social media is used is different between males and females, with the males primarily gaming, and the females using it primarily for social interaction and oftentimes not in a healthy way.

Elizabeth: On that note then, that’s a look at this week’s medical headlines from Texas Tech. I’m Elizabeth Tracey.

Rick: And I’m Rick Lange. Y’all listen up and make healthy choices.