Metformin and Congenital Abnormalities; Deprescribing in Patients With Dementia

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 metformin and congenital abnormalities, best meds for opioid use disorder treatment, deprescribing for patients with dementia, and tobacco use among U.S. youth.

Program notes:

0:37 Tobacco use among U.S. youth

1:34 One in 10 high school students

2:34 How much it costs to use tobacco

3:06 Paternal metformin use in men and offspring malformations

4:08 Corrected data showed no risk

5:08 Those who used metformin older

6:10 Treatment of opioid use disorder

7:10 Which is less likely to result in discontinuation

8:10 Mortality very low

9:03 Can we deprescribe in persons with dementia

10:03 Mailer to patient, physician or usual care

11:55 End

Transcript:

Elizabeth: Do we have to worry about men who take metformin and malformations in their children?

Rick: The best treatment for opioid use disorder.

Elizabeth: Can we safely take away medicines from people with dementia?

Rick: And tobacco product use among middle and high school students in the United States.

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: 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, let’s start with the good news in MMWR [Morbidity and Mortality Weekly Report]. Yikes, are we finally getting our arms around tobacco use?

Rick: We report on this annually and that’s because the National Youth Tobacco Survey conducts annual surveys that determine tobacco product use among U.S. middle school students grades 6 through 8, and high school students grades 9 through 12. I’m happy to report current use of tobacco products declined by an estimated 550,000 students between 2023 and 2024, largely driven by a decline in high school e-cigarette use, 1.56 million to 1.21 million students who reported that they used e-cigarettes anytime over the last 30 days. That’s the lowest level ever measured during a survey.

Even though there has been a decline in cigarette use, both e-cigarettes and combustible cigarette products, still one in 12 middle and high school students report current use. That’s about one in 10 high school students and one in 20 middle school students. This is when individuals get addicted to nicotine. Approximately two in five students who had ever used tobacco products still currently use them. E-cigarettes are the most commonly used products among both high school and middle school students. There has not really been a significant decline in middle school students’ use of e-cigarettes.

Elizabeth: Prohibitions against people who are younger than 21 in many places from purchasing any tobacco products, I think that’s helpful, and the constraints on flavored vaping products, which I was happy to see. I would sure like to see them make that even more robust. It’s always inexplicable to me why the FDA doesn’t really slam down because they have the authority.

Rick: I agree with you, which is that prohibiting their sale to minors is incredibly important and obviously the minors are getting them either because they are purchasing them illegally or they’re getting them from individuals that are allowed to purchase them. I do think that the national educational campaigns have been very helpful.

Elizabeth: I’m wondering about expenses and I really am totally lacking in any knowledge whatsoever on what it costs these days to support an average vaping habit or a combustible cigarette habit.

Rick: Unfortunately, this study doesn’t talk about it, and since neither you nor I buy tobacco products, we wouldn’t have first-hand knowledge. But I can tell you whatever it is, it’s not expensive enough.

Elizabeth: OK. I think that’s good. I’d like to see even more taxes applied to them so they become cost-prohibitive and people just decide voluntarily that they don’t want to spend their money in that direction.

Let’s turn to the BMJ. This is a look at paternal metformin use and the risk of congenital malformations in offspring. They note that, of course, global prevalence of type 2 diabetes is increasing and it’s increasing a lot in men of reproductive age, largely driven by obesity. They were looking for, hey, if we put these guys on metformin, is there going to be a higher rate of congenital malformations among their children?

These are two huge data sets during the period of sperm development, so 3 months before pregnancy, in a cohort in Norway and one in Taiwan — over 619,000 in a Norway cohort and 2.5 million+ in the Taiwan cohort — they were looking for these congenital abnormalities.

When they didn’t correct for anything, there was a modestly elevated risk for congenital abnormalities, specifically with organ malformations among these cohorts, but then once they corrected they weren’t able to see any risk whatsoever. So they say, gosh, let’s not worry about paternal use of metformin during spermatogenesis because we’re not really seeing an increased rate of these congenital malformations. And it’s really important, of course, to get these guys on something that’s going to help them manage their blood sugar.

Rick: I appreciate the rigors of this particular study and the large database that they pulled the data from because there was a Danish study previously published that suggested that men who used metformin preconception resulted in a 40% increased risk of congenital malformations in their children and primarily in male children. Whenever we see an association that doesn’t prove causality, we say is it biologically plausible? There really wasn’t any biologic plausibility.

What these investigators did, they said OK, as you said, it looked like there was a modest increase in metformin users, a modest increase in congenital malformations, but you have to compare directly populations that are very similar. Individuals who use metformin were older, they were more likely to have uncontrolled diabetes, more likely to have obesity, chronic conditions, drug use — all conditions associated with congenital malformations. You have to correct for those factors, and when they did that, metformin wasn’t responsible for the increased risk of congenital malformation. It was all these other confounding issues. This report should give us assurance that having men with type 2 diabetes receiving metformin doesn’t increase the risk that their children will have congenital malformations.

Elizabeth: They also note that the partners of these men were women who also were frequently overweight or obese, also had type 2 diabetes, so speaking of confounders, that’s a huge confounder.

Rick: Right. Whenever we report studies, we try to say OK, this is just an association and you have to worry about whether there are unmeasured confounders that we didn’t consider or they weren’t properly corrected.

Elizabeth: Let’s move to JAMA.

Rick: The best treatment for opioid use disorders. There are two FDA-approved major treatments available for individuals who have opioid use disorder in the United States — that’s the use of buprenorphine/naloxone, and that’s considered first-line treatment by many centers in the United States, and then the other one is methadone.

The reason why buprenorphine/naloxone has emerged as first-line treatment is there is thought that it has an increased safety profile, there is a shorter induction, and there is flexibility of take-home dosing schedules. Whereas most of the methadone centers in the United States, they personally appear, they only get a 30-day supply, and they thought that that would make methadone safer.

But what happened during COVID-19 is many of those restrictions were relaxed. People that were receiving methadone treatment already, we allowed them to take it at home. We have sent them more prescriptions. They didn’t have to report to centers. Then we looked at that data retrospectively, it looked like, hey, it was safe.

What these study investigators tried to determine is if you compare those two treatments — buprenorphine/naloxone versus methadone for the treatment of opioid use disorders — which of them is less likely to result in discontinuation of treatment among those who were first prescribed these medications for opioid use disorder or for those that have been on it for a period of time? They looked at over 31,000 new and prescribed individuals and about 25,600 it wasn’t their first time to be prescribed one or more of these medications.

What they determined was you were less likely to discontinue treatment if you were prescribed methadone than the other combination therapy for either particular group, and it was significant. You’re about 60% more likely to discontinue treatment if you were taking buprenorphine/naloxone than you were methadone. We need to reconsider how we are prescribing methadone because of these results.

Elizabeth: Was that the same rate of discontinuation for both groups irrespective of whether they were primary or secondary takers, if you will?

Rick: It is. There is about an 8-12 absolute percent difference in favor of methadone. By the way, they looked at mortality as well. What they discovered is the mortality in each of these arms was incredibly low, less than 0.1% in either arm.

Elizabeth: I’m also wondering about that factor that people who are in this world are so commonly citing, that’s abuse potential. I believe that there is a higher abuse potential with methadone, is that correct?

Rick: That was a concern, Elizabeth, if you prescribed methadone like you prescribe the other treatment is that it would result in increased mortality as a result of increased substance abuse. But these particular studies really don’t confirm that.

Elizabeth: Well, this is good news — I think this along with some of the other data we reported, of course — that for the first time for a while, the number of overdose deaths declined last year for the last year for which data was available. I think the availability of effective treatment and relaxing some of the barriers to obtaining it are really important factors.

Rick: I agree.

Elizabeth: Let’s move to JAMA Internal Medicine, speaking of medicines, and let’s take a look at, gosh, can we get high-risk medications in persons living with dementia deprescribed?

This is looking at folks with Alzheimer’s disease and Alzheimer’s disease-related dementias. As they progress in their disease, they may actually have a reduced requirement for some of these medicines that are useful earlier on and they also may become more sensitive for adverse outcomes relative to them. This study looks at antipsychotics, sedative-hypnotics, and strong anticholinergic agents. They wanted to see whether they sent a mailed educational intervention to both patients and caregivers, prescribers, or usual care, and see if that actually helped in deprescribing these high-risk medications. The population was two large national health plans. They had either the mailer to the patient and their caregiver, to their prescribing clinician, or the usual care arm. They had just shy of 13,000 patients who were included. They did not see any anti-prescribing in any of the arms that they looked at. This is a rather disappointing outcome for this strategy.

Rick: First of all, kudos to JAMA Internal Medicine for publishing this study because oftentimes negative studies don’t get published. Simply mailing out a single mailer to a physician or to the patient really doesn’t increase deprescribing.

Now, let’s take a step back for a couple of things. We don’t know if these patients actually had an indication for these medications. We live in an age where there is so much information overload. Just sending a text or sending a message by email, or mailing in the mail rarely gets somebody’s attention. But if you combine that with a personal touch, that in other studies has shown to be beneficial.

Elizabeth: They speculate, of course, in here on why that might be the case. One of their hypotheses is that people are reluctant, whether clinicians or caregivers, to change the regimen of folks with dementia because they are worried that if I take something away something might destabilize and then I’m going to have a whole host of other things to deal with.

Rick: It’s oftentimes not just the patient or the physician. It’s the caregiver as well that’s faced with taking care of an individual that has not only cognitive decline, but may have some behavioral issues and oftentimes they ask the doctor to prescribe these, even though they could be associated with increased harm to the patient.

Elizabeth: Yeah. This is a moving target. On that note, no doubt we’ll talk about this again. That’s a look at this week’s medical headlines from Texas Tech. I’m Elizabeth Tracey.

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

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