GLP-1 Agonists in Adolescents and Young Adults; Benefits of Cancer Drug Trials

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 early diagnosis and treatment of chronic obstructive pulmonary disease (COPD) and asthma, use of GLP-1 agonists in adolescents and young adults, implications of new lung function equations, benefits of cancer drug trials.

Program notes:

0:40 Implications of race adjustment in lung function equations

1:40 Over 12 million reclassified for lung function

2:40 Can be other confounders

3:40 Would differentiate race

4:40 There are race based conditions

5:00 Survival benefit with cancer clinical trials

6:00 Quality of the trials

7:00 Routinely apply guidelines

7:30 Dispensing GLP-1 agonists to young

8:30 Three approved for type 2 diabetes in adolescents

9:30 600% increase in use

10:05 Early diagnosis of COPD and asthma

11:05 Refer to pulmonologist

12:33 End

Transcript:

Elizabeth: What are the implications of new lung function equations?

Rick: Is there any survival benefit to people that participate in cancer drug trials?

Elizabeth: Prescribing of GLP-1 agonists to adolescents and young adults.

Rick: And does diagnosing and treating COPD and asthma really benefit?

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: Rick, if you don’t mind, I’d like to turn right to the New England Journal of Medicine and this question of “What are the implications of race adjustment in lung function equations?” This was something that was a novel concept to me, the notion that we would have equations that would assess lung function is not novel. However, the idea that they were really based on race or had pretty robust underpinnings relative to race was an absolutely new revelation to me.

There were these Global Lung Function Initiative (GLI) equations in 2012. They developed those worldwide and then they looked at this issue again with so-called “race-neutral equations” that were introduced in 2022. This study looks at, with these new equations, what are the implications for all the folks who are out there getting their lung function assessed?

They found that they would reclassify ventilatory impairment for over 12 million people, ratings of impairment for 8.16 million, occupational eligibility for over 2 million, grading of COPD for 2 million, and military disability compensation for over 400,000. These are largely identifying those of Black race as being, let’s call it, misclassified based on the old ones and with the new ones it would result in significant changes.

Rick: There are two things that the study did. Does it change classification? The second issue is, does it really predict overall outcomes? What they discovered is, as you said, it does change the classification — do you call someone severe or moderate or mild? In terms of overall outcomes, there was really no difference between the equations. Now, does it change the misclassification? Does it change the true false positives or false negatives? We really don’t know.

It’s interesting because we are trying to get away from race-based equations, because it assumes there is some hierarchy, and we realize that oftentimes there are other confounders. Here, for example, it’s age, it’s height, it’s weight, but I’m not sure that either one corrects misclassification. We just don’t know.

Elizabeth: Well, that’s an interesting point and I would say, based on these changes, it says that people who would be eligible — for example, for disability payments or who may or may not be allowed to apply to be a firefighter — that these things would be changed based on this new set of equations. I also would point out a statement I thought was really startling in the text of the paper. The authors say that historical use in quantifying presumed deficiencies in Black persons and justifying their enslavement, that’s their reference #7 in the references, and the reference is from 1860. I’m going to go back and look at it.

Rick: Right, and that was an era where we were looking for a number of things that would differentiate race, and particularly where it would make Blacks seem inferior or other races feel inferior compared to the white population that you and I are a part of, by the way. We have come to realize that these are social constructs that are just incorrect. There is no validity to them.

There is some deep-rooted history in that, and part of the reason we’re trying to get away from race-based equations is to get away from that altogether. Having said that, as you mentioned, if we change the criteria or based upon which equation we use, it says here the annual disability payments may increase by more than $1 billion among Black veterans and decrease by $0.5 billion among white veterans, so the classification does have some social implications.

Elizabeth: I would also like to note that a paper we did not discuss this week that’s in JAMA identified genetic variations that predispose Black people who have these particular variations to develop congestive heart failure. I think that throwing out this whole notion that there are these variations and that they can predict things, propensity to disease, or function is not a good idea.

Rick: Obviously, there are some race-based diseases; sickle cell happens to be one of them. This is different than using equations to justify changes in either healthcare outcomes or the application of diagnosis or treatments.

Let’s talk about cancer therapy since we’re talking about survival.

Elizabeth: Sure, let’s turn to JAMA.

Rick: This is titled “Survival Benefit Associated With Participation in Clinical Trials of Anticancer Drugs.” There is a belief among many individuals that patients achieve better clinical outcomes because they have participated in a clinical trial, and this is called the trial effect. Now, that trial effect really has two components. When someone enrolls in a trial, they do two things. They may receive the treatment or the placebo, and the other is they just participate in the trial. For those individuals that don’t receive the treatment, they still are in the trial — they receive the placebo — but they could receive some of the benefits of it. For example, having close follow-up and having regular labs drawn.

What these investigators did was they extracted data and did a quality assessment of 39 different publications that comprise 85 comparisons of trial participants and routine care patients. When they looked at it, overall it looked like there was a significant overall survival benefit for those who participated in the trial; it reduced mortality by about 24%. However, some of these trials were good quality trials. Some were not good quality trials. When they limited their investigation to just those that are high quality, it looked like their survival benefits disappeared.

They also looked at things called publication bias — that is, you’re more likely to publish the positive trials and not publish the negative trials. When they looked at that, there was no benefit at all.

Elizabeth: This is really kind of a startling finding, isn’t it? Because we have advocated for a long time for people to be participatory in clinical trials and expanded that model, including community-based oncologists who are able to treat patients per protocol, for example, without having them have to travel to academic medical centers. I am very interested in seeing what the reaction among the cancer cognoscenti is going to be to this paper.

Rick: Elizabeth, I’m sure that you will query them at Hopkins. The implication is that if you’re not in a clinical trial you receive substandard care. We know now that there are guidelines that identify what is the best care for people with different types of cancer and we can routinely apply those outside of clinical trials.

The second thing is people that participate in clinical trials are oftentimes not like those that we see in the real world. Oftentimes, they are healthier, they’re younger, they’re fitter; their overall outcome is better. Now, there are benefits to clinical trials. For people that have exhausted the benefits of routine therapy, they can go on a study drug. Overall, you can’t say that their survival is better.

Elizabeth: I think this is going to be an ongoing issue, Rick. I don’t think this is the last word even remotely.

Staying in JAMA, let’s turn to this notion of the dispensing of GLP-1 receptor agonists to adolescents and young adults. I’m really interested in this — of course, I know you are too — because the rate of obesity has just skyrocketed. How are we going to get our arms around this? And these drugs appear to be helpful with lots and lots of data coming out about their ability to help people lose weight and then actually keep it off interestingly. I’m also seeing a whole lot more information about even how to start the things than to optimize their use.

But in this case, this is a research letter that’s looking at, “How much are we really giving this to these adolescents, those aged 12 to 17, and young adults, those aged 18 to 25 years?” They used a database that looks at dispensing of these drugs and they queried between January 2020 and December 2023. They included five of the GLP-1 receptor agonists; three of them are approved for type 2 diabetes treatment in adolescents. All are approved for this indication in adults. They note that only two of them are approved for weight management in adolescents and adults.

They found that the number of adolescents and young adults who received these things increased from 8,700 in 2020 to over 60,000 in 2023. Females got this way more often than the males did and they also note the vast majority of dispensing of these drugs occurred in the U.S. South. Endocrinologists are dispensing them and also nurse practitioners are dispensing them. A question clearly that we have is, what’s the long-term impact of the use of these drugs in adolescents and young adults?

Rick: Particularly in the childbearing women as well because we don’t know about their safety. What you have described, Elizabeth, is over this 3-year period almost a 600% increase in the use of these medications. Some of it is due to the use of the injectable form of these GLP-1s for treatment of type 2 diabetes and some for weight. Both have seen a dramatic increase, specifically since the beginning of 2023.

It looks like we are going to get a lot more information in the next several years just because of the massive increase in the use of these medications. Let alone, by the way, we haven’t talked about the economic cost or the societal cost because these are not inexpensive medications.

Elizabeth: Right. They do note in here that these are largely paid by Medicaid, so that’s going to be a public health cost that we’re all going to have to factor in. Let’s turn to your final one and that’s back in the New England Journal of Medicine.

Rick: Early diagnosis and treatment of chronic obstructive pulmonary disease (COPD) and asthma provide a benefit.

We’re talking about the 5% of individuals that have this and that it’s not really been detected. They don’t have severe symptoms and they normally wouldn’t even come to medical attention. How do these investigators find these individuals and then provide them either treatment with a pulmonologist or just the knowledge that they have these diseases? Does it reduce healthcare utilization?

Rather than screening the whole population, they directed it towards individuals that have respiratory symptoms. They just randomly called people and said, “Does anybody in the home have respiratory symptoms?” If the answer was yes, then they did spirometry. On the basis of that, after screening about 38,000 individuals, they had just over 500 that had been underdiagnosed and they either just gave them that information or they referred them to a pulmonologist to initiate very early therapy.

What they discovered was if they could identify and treat it early, in fact, it did reduce healthcare utilization by about 50%. It decreased hospitalization as well and overall the quality of life was better. Those that had the lowest healthcare utilization were those that were referred to a pulmonologist to initiate early care.

Elizabeth: That clearly is a place where that’s going to be a sticking point because the density of pulmonologists across the country is very uneven.

Rick: It is. It suggests that even allowing the individual to know they can initiate treatment with their primary care physician, there was some improvement.

Elizabeth: It sounds like more specific diagnosis results in better outcomes.

Rick: More specific and, again, the way they found these cases is they didn’t just screen the general population — that’s really not cost-effective — but limited it to people with pulmonary symptoms.

Elizabeth: On that note then, that’s the 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.

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