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GLP-1 RA Therapy for Alcohol Use Disorder?
This transcript has been edited for clarity.
Akshay B. Jain, MD: Today we are very excited to have Dr. Leggio join us all the way from the National Institutes of Health (NIH). He is an addiction physician scientist in the intramural research program at NIH. Welcome, Dr. Leggio. Thanks for joining us.
Lorenzo Leggio, MD, PhD: Thank you so much.
Dr. Jain: We’ll get right into this. Your session was, in my mind, extremely informative. The session looked at glucagon-like peptide 1 receptor agonist (GLP-1 RA) therapy and its potential effects on mitigating alcohol misuse syndrome, so, reduction of alcohol addiction potentially.
We’ve seen in some previous clinical trials, including many from your group, that alcohol use is known to be reduced — the overall risk of incidence, as well as recurrence of alcohol use — in individuals who are on GLP-1 RA therapy.
Can you share more insights about the data already out there?
Dr. Leggio: At the preclinical level, we have a very robust line of studies, experiments, and publications looking at the effect of GLP-1 RAs, starting from exenatide up to, more recently, semaglutide. They show that these GLP-1 RAs do reduce alcohol drinking. They used different animal models of excessive alcohol drinking, using different species — for example, mice, rats, nonhuman primates — models that reflect the excessive alcohol drinking behavior that we see in patients, like physical alcohol dependence or binge-like alcohol drinking, and other behaviors in animal models that reflect the human condition.
In addition to that, we recently have seen an increase in human evidence that GLP-1 RAs may reduce alcohol drinking. For example, there is some anecdotal evidence and some analyses using social media showing that people on GLP-1 RAs report drinking less alcohol.
There are also some pharmacoepidemiology studies which are very intriguing and quite promising. In this case, people have been looking at electronic medical records; they have used the pharmacoepidemiology approaches to match patients on GLP-1 RAs because of diabetes or obesity, and have compared and matched to patients on different drugs as the controls.
A study was recently published Nature Communications by a group in Cleveland in collaboration with Dr. Nora Volkow from the National Institute on Drug Abuse. This study shows the association between being on a GLP-1 RA and the lower incidence of alcohol use disorder and lower drinking.
There is also some promise from prospective randomized clinical trials. In particular, there was one clinical trial from Denmark, a well-known and -conducted clinical trial where they looked at exenatide, and they didn’t see an effect of exenatide compared with placebo in the main analysis. But in a subanalysis, they did see that exenatide reduced alcohol drinking, but only in patients with alcohol use disorder and obesity.
This suggests that these medications may work for some patients and not for other patients. That’s fine, because just like in any other field in medicine, including diabetes, obesity, hypertension, Parkinson’s, and depression, not all medications work for everybody. If these medications will work for alcohol addiction, we do not expect that they will work for everybody.
One ongoing question in the field is to try to identify the phenotypes or the subgroup of people who may be more responsive to these medications.
Dr. Jain: This is such a fascinating field, and all these studies are coming out. In your review of all the literature so far, do you think this is dose dependent? Also, we see that, for instance, with certain individuals, when they take GLP-1 RA therapy, they might have a lot of gastrointestinal (GI) side effects. Recent studies have shown that the rate of these GI side effects does not necessarily correlate with the amount of weight loss. In the alcohol addiction field, do you think that the GI side effects, things like nausea, could also have a potential role in mitigating the alcohol addiction?
Dr. Leggio: This is a great question. They may play a role; they may contribute, too, but we don’t think that they are the driving mechanism of why people drink less, for at least a couple of reasons.
One is that, similar to the obesity field, the data we have so far don’t necessarily show a relationship between the GI side effects and the reduction in drinking. Plus, the reduction in drinking is likely to happen later when many GI side effects are gone or attenuated.
The second reason is from the neuroscience field. We are starting to better understand the mechanism at the brain level as to how these medications work. We don’t see that the nausea or, more generally, not feeling well — malaise, etc. — are driving mechanisms for how these medications work.
Again, it’s not to discount completely that the GI side effects may play a role, but I would say that, if anything, they may be more contributing to. And if they do, that will not be unique to this class of medication. For example, we have three medications approved by the US Food and Drug Administration (FDA) for alcohol use disorder.
One challenge we have in the addiction field is that many people don’t know that these medications exist — many primary care providers don’t know — and they are completely underutilized. Everybody here who is listening to us knows that roughly 85% of people with diabetes receive a medication for diabetes. For alcohol use disorder, the number is 2%. These are medications approved by the FDA.
One of them is naltrexone, which does give GI symptoms — in particular, nausea and vomiting. The other medication is acamprosate, which does give diarrhea.
You have medications approved for alcohol disorder where you do have some GI symptoms, but they are not the mechanism either for how these medications help people to curb craving and reduce alcohol drinking.
Dr. Jain: What about the dose-dependent action? Do you think that GLP-1 RAs, at a lower dose, may not have an effect on alcohol use disorder vs at a higher dose, or is everyone a little different?
Dr. Leggio: That’s a wonderful question. The short answer is, we don’t know, to be honest. Now, in some of the animal studies — my team has been in collaboration with other scientists in the NIH intramural research program, and also with scientists in academia, for example, at Scripps, UCLA — we see a dose response where the higher the dose, the higher the effect of the drug. In this case, semaglutide reduced binge drinking in a rat model of a physical alcohol dependence.
That said, I would be very cautious about claiming, based on the rodent data, that humans will have a dose response. It’s an open question. We really don’t know. Some of the pharmacoepidemiology data suggested that even lower doses — for example, using semaglutide for diabetes without going up to the obesity dose — may be just as effective as a higher dose in reducing the incidence of alcohol use disorder.
It’s important also to keep in mind that the pharmacoepidemiology data are always an association. Reduction in alcohol disorder is associated with the prescription GLP-1 RA, but they don’t really replace the more gold-standard, double-blind, placebo-controlled randomized clinical trial. Nonetheless, with the pharmacoepidemiology data, I think there is an argument to at least hypothesize that people may respond well, even to lower doses.
This also may be important from a safety standpoint.
Basically, we need to wait for results in the next years to come from randomized clinical trials to better unfold the question about doses. For example, just anecdotally, I will tell you that in the clinical trial we are conducting right now at the NIH Intramural Research Program, for which I’m the principal investigator (PI), we are going up to 2.4 mg — the highest dose of semaglutide.
We are collaborating with Kyle Simmons, PhD, from Oklahoma State University. Our two studies are not like a two-site clinical trial, but they are harmonized. In Dr. Simmons’ clinical trial, they’re going up to 1.0 mg. We are excited about this team approach because the trials are slightly different, but they’re harmonized to the point that, once the studies are done, we’ll be able to combine and compare data to better answer the question about dosing, and many other questions.
Dr. Jain: From a clinical perspective, we see that many people who are battling alcohol use disorder may not have obesity. They might actually be on the leaner side, and hence, we may not want to use a high dose of GLP-1 RA therapy. It’ll be very exciting to see when these results come out.
This brings me to the next question. I think everyone would love to know why this happens. Why is GLP-1 RA having this effect on alcohol use disorder? I know that your group has done many animal studies, as you pointed out, and one of the postulated theories was the effect on the GABA neurotransmission pathway.
Can you tell us more about what you feel is the underlying mechanism of action here?
Dr. Leggio: I will start by saying that we don’t fully know. There are many open questions. If I can sidetrack for one second: We come up with the idea that, first of all, alcohol use disorder and substance use disorder are addictive behaviors, addictive disorders. We define addiction as a brain disease.
Granted that addiction is a brain disease, it doesn’t mean that addiction works just in the brain in isolation. As we all know, the brain works in concert with the rest of the body. One specific approach my team has been taking is working on the analogy and the similarities between obesity and addiction to try to understand how the body-brain connection, such as the gut-brain-neuroendocrine pathway, may play a role in patients with addiction.
With that in mind, a large amount of work in my lab in the past 20 years — since I’ve been a PI — has been focused on studying this neuroendocrine pathways related to the gut-brain axis. For example, we have done work on insulin and leptin, primarily; we had done work on ghrelin, and since 2015 on the GLP-1 RAs.
With that in mind, the framework we are working on, which is also substantiated by many studies done by our team and other teams in the neuroscience field, kind of supports the idea that, similar to what we see in obesity, these medications may work by affecting what we call reward processing, or the seeking for addictive drugs, such as alcohol, and also the drugs such as the stimulants, opioids, nicotine, and so on.
The idea is that the mechanism is driven by the ability of the medication — semaglutide and all the GLP-1 RAs — to reduce the rewarding properties of alcohol and drugs. To maybe make the example more pragmatic, what does that mean? It means, for example, that a patient who typically has 10 drinks per day in the afternoon and night, while they are on the medication they may feel the lack of need to drink up to 10 to feel the same reward.
They may be able to stop after two or three drinks, which means a significant harm reduction and a beneficial outcome. This also brings us to another mechanism, which may be related to society. We don’t fully understand how much the society mechanism, including society mechanism related to GI motility, may also play a role.
With that said, we don’t think that the effect of the GLP-1 RAs is merely due to alcohol being a calorie-based nutrient because, in fact, we see alcohol as an addictive drug, not as a nutrient. Also, the GLP-1 RAs, at least in animal models, seem to work on other addictive drugs that don’t have calories, such as nicotine, and possibly with cannabis, opioids, and stimulants.
Then on the molecular level, our team recently showed, in collaboration with Dr. Marisa Roberto from Scripps in La Jolla, California, that semaglutide may in fact change the GABA transmission at the level of some brain regions, such as the amygdala and the prefrontal cortex. These are brain regions that are well-established hubs that play a role in the mechanism underlying addiction.
There are also some very exciting recent data showing how these medications may work not just on GABA or just on dopamine, which is the canonical way we conceive of reward processing, but by working on both by modulating GABA transmission — for example, at the ventral tegmental area and dopamine transmission at the nucleus accumbens.
Bottom line, if I summarize all of this, is that the mechanism is not fully understood, but there is definitely a contribution of this medication to effect and reward processing, possibly by altering the balance between GABA and dopamine. There are still some unknown questions, such as, are these mechanisms all brain driven or are they signaling from the periphery to the brain, or maybe both?
Also, as we all know, there are many differences across all these GLP-1 analogs in brain penetrance. Whether the drug needs to go to the brain to have an effect on alcohol drinking, cocaine seeking, or smoking is really an open question.
Dr. Jain: This is so thought-provoking. I guess the more we uncover, the more mesmerized we get with all the potential crosstalk. There is a large amount of overlap in the brain with each of these different things and how it all interplays with each other.
Speaking of interplay, I’m thinking about how many people prone to having alcohol use disorder can potentially develop complications, one of these being chronic pancreatitis. This is a well-known complication that can occur in people having alcohol addiction. Along that same line, we know that previous history of pancreatitis is considered a use-with-caution, or we don’t want to use GLP-1 RA therapy in people who have had pancreatitis.
Now it becomes this quagmire where people may have chronic pancreatitis, but we may want to consider GLP-1 RA therapy for management of alcohol use disorder. What are your thoughts about this, and the safety, potentially, in using it in these patients?
Dr. Leggio: This is another wonderful question. That’s definitely a top priority in our mind, to address these kinds of questions. For example, our RCT does have, as core primary outcomes, not only the efficacy defined as a reduction in alcohol drinking, but also safety.
The reason is exactly what you just explained. There are many unanswered questions, including whether giving a GLP-1 RA and alcohol together may have synergistic effects and increase the likelihood of having pancreatitis.
The good news is that, so far, based on the published literature, including the RCT done with exenatide in Denmark and published in 2022 and also the ongoing clinical trials — including my own clinical trial, but of course we are blind — pancreatitis has not been coming out as an adverse event.
However, it’s also true that it often happens in clinical medication development. Of course, we screen and select our population well. For example, we do exclude people who have a history of pancreatitis. We exclude people with high lipase or with any of the clinical symptomatology that makes us concerned about these people having pancreatitis.
As often happens when you move a medication from clinical trials to clinical practice, we still need to understand whether this medication works in patients. I’m just speculating, but even if the clinical trials do not raise red flags in terms of increased risk for some side effects such as pancreatitis, I think it will be very important for practitioners to keep a close eye on the death risk regardless.
It’s very interesting that it’s similar to alcohol liver disease. With pancreatitis, not every single patient with alcohol addiction has pancreatitis. We don’t really fully understand why some people develop pancreatitis and some people do not. The point being that there are many patients with alcohol addiction who don’t have pancreatitis and may benefit from these medications if they work. Again, we have to prove that in patients.
On the other side, as we all know, pancreatitis is a potentially life-threatening condition for those people who either have it or are at risk for it. I think we have to be very careful before we consider giving them a GLP-1 RA.
One could argue that alcohol is the leading cause of mortality and morbidity in the world. For example, right now, alcohol is the leading cause of liver disease. It’s the main reason for liver transplantation in our country. Alcohol is affecting thousands of people in terms of death and emergency room visits.
You could argue that the downside is not treating these people and they die because of alcohol addiction. A GLP-1 RA is not going to be for everybody. I will remind everybody that (1) we do have FDA-approved medications for alcohol addiction; and (2) there are also other medications not approved by the FDA, but with a proven efficacy in some clinical trials — for example, topiramate and gabapentin — and they’ve been endorsed by the American Psychiatric Association.
There is also some evidence for another medication, baclofen, which has been endorsed by the American College of Gastroenterology for patients with alcohol addiction and liver disease.
The point I’m making is that it’s not that either we use the GLP-1 RAs or we have no other tools. We have other tools. I think we have to personalize the treatment based on the patient’s profile from a safety standpoint and from a phenotypic standpoint.
Dr. Jain: I love that thought. I think individualization is the key here.
We know that people with diabetes have a higher risk for pancreatitis by virtue of having diabetes. People with obesity also have a higher risk for pancreatitis by virtue of having obesity. These are the two conditions where we are using a large amount of GLP-1 RA therapy. Again, the idea is looking at the person in front of us and then deciding, based on their past medical history and their current risk, whether or not a medication is a right fit for them.
I think more individualization here will come as we start using these medications that might be having potential effects on different organ systems. You mentioned a little bit about the liver, so a thought came in my mind. We know that people with diabetes who have alcohol use disorder are at a higher risk for potential hypoglycemia. If they have events when they have increased consumption of alcohol, there can be more hypoglycemia.
We now could potentially be using semaglutide or other GLP-1 RA therapy for management of alcohol use disorder. In your own experience in the studies that you’ve done or the literature that’s out there, has that been associated with an even higher risk for hypoglycemia?
Dr. Leggio: It’s a wonderful question. I’m not aware of any formal and published report of that association. That said, your thinking from a physiopathologist standpoint makes total sense. I could not agree more. The fact that nothing has been published, at least to my knowledge, doesn’t mean that the death risk doesn’t exist. In fact, I agree with you that it does exist.
Alcohol use disorder is interesting and tricky clinically because chronically, alcohol addiction or alcohol use disorder is associated with an increased risk for diabetes. Acutely, as you point out; and this could be with or without alcohol use disorder. An episode of a high volume of binge drinking may lead to hypoglycemia.
This is one of the reasons why people may show up to the emergency room with intoxication, and one of the symptoms detected at the emergency room is that they also have hypoglycemia in addition to vomiting, nausea, and everything else that we see in patients with acute intoxication.
Similar to the discussion about pancreatitis, as we work on understanding the possible role of GLP-1 RA in patients with alcohol use disorder, we do have to keep a close eye on the risk for hypoglycemia. The short answer is that this is not well established, but based on the simple concept of “first, do no harm,” I think we need to track that very carefully.
In the ongoing clinical trial we’re doing in Maryland in my program at the NIH, we do just that. We are tracking glucose levels. Of course, patients come to clinic weekly, so unless they have symptoms, typically we don’t see anything at the time.
More important, we educate our patients when they go through the consent process. We tell them that this medication per se does not give hypoglycemia. In fact, we’re including people with diabetes, so for people on other medications like metformin, we explain to them that technically such a risk should not exist, but because you’re drinking alcohol in excessive amounts, you do have a potential higher risk. We just don’t know how significant that risk could be.
We do a large amount of education at baseline when they enroll in our study. We also educate our patients on how to recognize early on the potential risk for hypoglycemia, exactly for the reasons you said. We explain to them the unknown potential that the GLP-1 RAs and alcohol together may synergize and give hypoglycemia.
Dr. Jain: I don’t know if you got this feeling at the ADA conference, but I felt, when attending all these sessions, that it seems like GLP-1 RA is the gift that keeps giving. We see the effect on diabetes, obesity, metabolic-associated steatotic liver disease, possibly with Alzheimer’s, chronic obstructive pulmonary disease, and so many things.
Now, of course, there’s potential use in alcohol use disorder. Do you think that using GLP-1 RA therapy is ready for prime time? Do you think we are now ready to prescribe this in people with alcohol use disorder?
Dr. Leggio: I would say we’re not there yet. As I mentioned at the beginning, the evidence keeps on growing. It’s getting stronger and stronger because the positive data keep on coming up. We have data from animal models, including the different species, ranging from rodents to nonhuman primates. We have anecdotal evidence and machine-learning approaches using, for example, big data and social media data. Now we have pharmacoepidemiology data and some small, initial, but still good randomized clinical trials.
What we are missing is the final step of having a substantial number of prospective, double-blind, placebo-controlled clinical trials to really prove or disprove whether these medications work, and to also better understand which patients may respond to these medications.
The good news is that there are many ongoing clinical trials. We are conducting a clinical trial in Maryland at the NIH. Dr. Simmons is doing a clinical trial at Oklahoma State University. Dr. Christian Hendershot at UNC is conducting a study at Chapel Hill. Dr. Josh Gowin is doing a study in Colorado. Dr. Anders Fink-Jensen is doing a study in Denmark. The momentum is very high.
I’m only mentioning those people who are doing alcohol-semaglutide clinical trials. There are also people doing clinical trials on smoking, stimulants, and opioids. There are actually some very fresh, still unpublished data from Penn State that were presented publicly at conferences, showing how these drugs may reduce opioid craving, which is, of course, critically important, given that we’re in the middle of a fentanyl pandemic that is killing one person every 7 minutes, for example, in Baltimore. It’s very alarming and we need more treatments.
The bottom line is that it’s very promising, but we need to wait for these clinical trials to have a definitive answer. I would say that if you have a patient with diabetes, obesity, and also alcohol addiction, and they are on semaglutide or any other GLP-1 RA, and in addition to using the medication for diabetes and obesity, they also have a beneficial effect on their alcohol drinking, then that’s fantastic. At the end of the day, that’s the mission we all share: helping people.
If it’s someone without obesity and diabetes, personally, at this stage, I will go with other medications that either have FDA approval or at least very solid evidence of efficacy from RCTs rather than going with the GLP-1 RA, at least until I see more definitive data from randomized clinical trials.
There is a large amount of hope. We are hoping that these clinical trials will be positive. We are very enthusiastic and we’re also very thrilled to see that Novo Nordisk recently launched a gigantic multisite clinical trial with — I forgot how many sites, but it’s very large across Europe, America, and maybe other continents as well.
Their primary outcome is improvement in alcohol-related liver disease, but they’re also looking at alcohol drinking as a secondary outcome. That’s very important because, unlike in the diabetes field, in the addiction field, we do struggle to build partnership with the private sector because sometimes the addiction field is not seen as an appetitive field from pharma.
We all know that the best success in any medication development story is when you put academia, the government, and pharma together. Think about the COVID-19 vaccine development. That’s unfortunately the exception rather than rule in the addiction field.
With the company doing a large clinical trial in the alcohol field, although they focus more on the liver but they also looked at drinking, I really hope we’ll see more and more companies in the private sector take more and more interest in addiction. Also, I hope to see more and more partnership between the private sector, the government, and academia.
Dr. Jain: Such exciting times, indeed. We can’t wait enough for the results of these and many other trials to come out. Dr. Leggio, it was an absolute delight chatting with you today. Thank you so much for joining us from ADA 2024.
Akshay B. Jain, MD, Clinical Instructor, Department of Endocrinology, University of British Columbia; Endocrinologist, TLC Diabetes and Endocrinology, Vancouver, British Columbia, Canada, has disclosed the following relevant financial relationships: Serve(d) as a speaker or a member of a speakers bureau for: Abbott; Acerus; AstraZeneca; Amgen; Bausch Healthcare; Bayer; Boehringer Ingelheim; Care to Know; CCRN; Connected in Motion; CPD Network; Dexcom; Diabetes Canada; Eli Lilly; GSK; HLS Therapeutics; Janssen; Master Clinician Alliance; MDBriefcase; Merck; Medtronic; Moderna; Novartis; Novo Nordisk; Partners in Progressive Medical Education; Pfizer; Sanofi Aventis; Timed Right; WebMD. Received research grants/research support from: Abbott; Amgen; Novo Nordisk. Received consulting fees from: Abbott; Acerus; AstraZeneca; Amgen; Bausch Healthcare; Bayer; Boehringer Ingelheim; Dexcom; Eli Lilly; Gilead Sciences; GSK; HLS Therapeutics; Insulet; Janssen; Medtronic; Novo Nordisk; Partners in Progressive Medical Education; PocketPills; Roche; Sanofi Aventis; Takeda. Lorenzo Leggio, MD, PhD, Clinical Director, Deputy Scientific Director, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Baltimore, Maryland, has disclosed the following relevant financial relationships: Serve(d) as a US federal employee for: National Institutes of Health. He had received income in an amount equal to or greater than $250 from: UK Medical Council on Alcohol for his service as editor-in-chief for Alcohol and Alcoholism and received royalties from Rutledge as an editor for a textbook.
A version of this article first appeared on Medscape.com.
This transcript has been edited for clarity.
Akshay B. Jain, MD: Today we are very excited to have Dr. Leggio join us all the way from the National Institutes of Health (NIH). He is an addiction physician scientist in the intramural research program at NIH. Welcome, Dr. Leggio. Thanks for joining us.
Lorenzo Leggio, MD, PhD: Thank you so much.
Dr. Jain: We’ll get right into this. Your session was, in my mind, extremely informative. The session looked at glucagon-like peptide 1 receptor agonist (GLP-1 RA) therapy and its potential effects on mitigating alcohol misuse syndrome, so, reduction of alcohol addiction potentially.
We’ve seen in some previous clinical trials, including many from your group, that alcohol use is known to be reduced — the overall risk of incidence, as well as recurrence of alcohol use — in individuals who are on GLP-1 RA therapy.
Can you share more insights about the data already out there?
Dr. Leggio: At the preclinical level, we have a very robust line of studies, experiments, and publications looking at the effect of GLP-1 RAs, starting from exenatide up to, more recently, semaglutide. They show that these GLP-1 RAs do reduce alcohol drinking. They used different animal models of excessive alcohol drinking, using different species — for example, mice, rats, nonhuman primates — models that reflect the excessive alcohol drinking behavior that we see in patients, like physical alcohol dependence or binge-like alcohol drinking, and other behaviors in animal models that reflect the human condition.
In addition to that, we recently have seen an increase in human evidence that GLP-1 RAs may reduce alcohol drinking. For example, there is some anecdotal evidence and some analyses using social media showing that people on GLP-1 RAs report drinking less alcohol.
There are also some pharmacoepidemiology studies which are very intriguing and quite promising. In this case, people have been looking at electronic medical records; they have used the pharmacoepidemiology approaches to match patients on GLP-1 RAs because of diabetes or obesity, and have compared and matched to patients on different drugs as the controls.
A study was recently published Nature Communications by a group in Cleveland in collaboration with Dr. Nora Volkow from the National Institute on Drug Abuse. This study shows the association between being on a GLP-1 RA and the lower incidence of alcohol use disorder and lower drinking.
There is also some promise from prospective randomized clinical trials. In particular, there was one clinical trial from Denmark, a well-known and -conducted clinical trial where they looked at exenatide, and they didn’t see an effect of exenatide compared with placebo in the main analysis. But in a subanalysis, they did see that exenatide reduced alcohol drinking, but only in patients with alcohol use disorder and obesity.
This suggests that these medications may work for some patients and not for other patients. That’s fine, because just like in any other field in medicine, including diabetes, obesity, hypertension, Parkinson’s, and depression, not all medications work for everybody. If these medications will work for alcohol addiction, we do not expect that they will work for everybody.
One ongoing question in the field is to try to identify the phenotypes or the subgroup of people who may be more responsive to these medications.
Dr. Jain: This is such a fascinating field, and all these studies are coming out. In your review of all the literature so far, do you think this is dose dependent? Also, we see that, for instance, with certain individuals, when they take GLP-1 RA therapy, they might have a lot of gastrointestinal (GI) side effects. Recent studies have shown that the rate of these GI side effects does not necessarily correlate with the amount of weight loss. In the alcohol addiction field, do you think that the GI side effects, things like nausea, could also have a potential role in mitigating the alcohol addiction?
Dr. Leggio: This is a great question. They may play a role; they may contribute, too, but we don’t think that they are the driving mechanism of why people drink less, for at least a couple of reasons.
One is that, similar to the obesity field, the data we have so far don’t necessarily show a relationship between the GI side effects and the reduction in drinking. Plus, the reduction in drinking is likely to happen later when many GI side effects are gone or attenuated.
The second reason is from the neuroscience field. We are starting to better understand the mechanism at the brain level as to how these medications work. We don’t see that the nausea or, more generally, not feeling well — malaise, etc. — are driving mechanisms for how these medications work.
Again, it’s not to discount completely that the GI side effects may play a role, but I would say that, if anything, they may be more contributing to. And if they do, that will not be unique to this class of medication. For example, we have three medications approved by the US Food and Drug Administration (FDA) for alcohol use disorder.
One challenge we have in the addiction field is that many people don’t know that these medications exist — many primary care providers don’t know — and they are completely underutilized. Everybody here who is listening to us knows that roughly 85% of people with diabetes receive a medication for diabetes. For alcohol use disorder, the number is 2%. These are medications approved by the FDA.
One of them is naltrexone, which does give GI symptoms — in particular, nausea and vomiting. The other medication is acamprosate, which does give diarrhea.
You have medications approved for alcohol disorder where you do have some GI symptoms, but they are not the mechanism either for how these medications help people to curb craving and reduce alcohol drinking.
Dr. Jain: What about the dose-dependent action? Do you think that GLP-1 RAs, at a lower dose, may not have an effect on alcohol use disorder vs at a higher dose, or is everyone a little different?
Dr. Leggio: That’s a wonderful question. The short answer is, we don’t know, to be honest. Now, in some of the animal studies — my team has been in collaboration with other scientists in the NIH intramural research program, and also with scientists in academia, for example, at Scripps, UCLA — we see a dose response where the higher the dose, the higher the effect of the drug. In this case, semaglutide reduced binge drinking in a rat model of a physical alcohol dependence.
That said, I would be very cautious about claiming, based on the rodent data, that humans will have a dose response. It’s an open question. We really don’t know. Some of the pharmacoepidemiology data suggested that even lower doses — for example, using semaglutide for diabetes without going up to the obesity dose — may be just as effective as a higher dose in reducing the incidence of alcohol use disorder.
It’s important also to keep in mind that the pharmacoepidemiology data are always an association. Reduction in alcohol disorder is associated with the prescription GLP-1 RA, but they don’t really replace the more gold-standard, double-blind, placebo-controlled randomized clinical trial. Nonetheless, with the pharmacoepidemiology data, I think there is an argument to at least hypothesize that people may respond well, even to lower doses.
This also may be important from a safety standpoint.
Basically, we need to wait for results in the next years to come from randomized clinical trials to better unfold the question about doses. For example, just anecdotally, I will tell you that in the clinical trial we are conducting right now at the NIH Intramural Research Program, for which I’m the principal investigator (PI), we are going up to 2.4 mg — the highest dose of semaglutide.
We are collaborating with Kyle Simmons, PhD, from Oklahoma State University. Our two studies are not like a two-site clinical trial, but they are harmonized. In Dr. Simmons’ clinical trial, they’re going up to 1.0 mg. We are excited about this team approach because the trials are slightly different, but they’re harmonized to the point that, once the studies are done, we’ll be able to combine and compare data to better answer the question about dosing, and many other questions.
Dr. Jain: From a clinical perspective, we see that many people who are battling alcohol use disorder may not have obesity. They might actually be on the leaner side, and hence, we may not want to use a high dose of GLP-1 RA therapy. It’ll be very exciting to see when these results come out.
This brings me to the next question. I think everyone would love to know why this happens. Why is GLP-1 RA having this effect on alcohol use disorder? I know that your group has done many animal studies, as you pointed out, and one of the postulated theories was the effect on the GABA neurotransmission pathway.
Can you tell us more about what you feel is the underlying mechanism of action here?
Dr. Leggio: I will start by saying that we don’t fully know. There are many open questions. If I can sidetrack for one second: We come up with the idea that, first of all, alcohol use disorder and substance use disorder are addictive behaviors, addictive disorders. We define addiction as a brain disease.
Granted that addiction is a brain disease, it doesn’t mean that addiction works just in the brain in isolation. As we all know, the brain works in concert with the rest of the body. One specific approach my team has been taking is working on the analogy and the similarities between obesity and addiction to try to understand how the body-brain connection, such as the gut-brain-neuroendocrine pathway, may play a role in patients with addiction.
With that in mind, a large amount of work in my lab in the past 20 years — since I’ve been a PI — has been focused on studying this neuroendocrine pathways related to the gut-brain axis. For example, we have done work on insulin and leptin, primarily; we had done work on ghrelin, and since 2015 on the GLP-1 RAs.
With that in mind, the framework we are working on, which is also substantiated by many studies done by our team and other teams in the neuroscience field, kind of supports the idea that, similar to what we see in obesity, these medications may work by affecting what we call reward processing, or the seeking for addictive drugs, such as alcohol, and also the drugs such as the stimulants, opioids, nicotine, and so on.
The idea is that the mechanism is driven by the ability of the medication — semaglutide and all the GLP-1 RAs — to reduce the rewarding properties of alcohol and drugs. To maybe make the example more pragmatic, what does that mean? It means, for example, that a patient who typically has 10 drinks per day in the afternoon and night, while they are on the medication they may feel the lack of need to drink up to 10 to feel the same reward.
They may be able to stop after two or three drinks, which means a significant harm reduction and a beneficial outcome. This also brings us to another mechanism, which may be related to society. We don’t fully understand how much the society mechanism, including society mechanism related to GI motility, may also play a role.
With that said, we don’t think that the effect of the GLP-1 RAs is merely due to alcohol being a calorie-based nutrient because, in fact, we see alcohol as an addictive drug, not as a nutrient. Also, the GLP-1 RAs, at least in animal models, seem to work on other addictive drugs that don’t have calories, such as nicotine, and possibly with cannabis, opioids, and stimulants.
Then on the molecular level, our team recently showed, in collaboration with Dr. Marisa Roberto from Scripps in La Jolla, California, that semaglutide may in fact change the GABA transmission at the level of some brain regions, such as the amygdala and the prefrontal cortex. These are brain regions that are well-established hubs that play a role in the mechanism underlying addiction.
There are also some very exciting recent data showing how these medications may work not just on GABA or just on dopamine, which is the canonical way we conceive of reward processing, but by working on both by modulating GABA transmission — for example, at the ventral tegmental area and dopamine transmission at the nucleus accumbens.
Bottom line, if I summarize all of this, is that the mechanism is not fully understood, but there is definitely a contribution of this medication to effect and reward processing, possibly by altering the balance between GABA and dopamine. There are still some unknown questions, such as, are these mechanisms all brain driven or are they signaling from the periphery to the brain, or maybe both?
Also, as we all know, there are many differences across all these GLP-1 analogs in brain penetrance. Whether the drug needs to go to the brain to have an effect on alcohol drinking, cocaine seeking, or smoking is really an open question.
Dr. Jain: This is so thought-provoking. I guess the more we uncover, the more mesmerized we get with all the potential crosstalk. There is a large amount of overlap in the brain with each of these different things and how it all interplays with each other.
Speaking of interplay, I’m thinking about how many people prone to having alcohol use disorder can potentially develop complications, one of these being chronic pancreatitis. This is a well-known complication that can occur in people having alcohol addiction. Along that same line, we know that previous history of pancreatitis is considered a use-with-caution, or we don’t want to use GLP-1 RA therapy in people who have had pancreatitis.
Now it becomes this quagmire where people may have chronic pancreatitis, but we may want to consider GLP-1 RA therapy for management of alcohol use disorder. What are your thoughts about this, and the safety, potentially, in using it in these patients?
Dr. Leggio: This is another wonderful question. That’s definitely a top priority in our mind, to address these kinds of questions. For example, our RCT does have, as core primary outcomes, not only the efficacy defined as a reduction in alcohol drinking, but also safety.
The reason is exactly what you just explained. There are many unanswered questions, including whether giving a GLP-1 RA and alcohol together may have synergistic effects and increase the likelihood of having pancreatitis.
The good news is that, so far, based on the published literature, including the RCT done with exenatide in Denmark and published in 2022 and also the ongoing clinical trials — including my own clinical trial, but of course we are blind — pancreatitis has not been coming out as an adverse event.
However, it’s also true that it often happens in clinical medication development. Of course, we screen and select our population well. For example, we do exclude people who have a history of pancreatitis. We exclude people with high lipase or with any of the clinical symptomatology that makes us concerned about these people having pancreatitis.
As often happens when you move a medication from clinical trials to clinical practice, we still need to understand whether this medication works in patients. I’m just speculating, but even if the clinical trials do not raise red flags in terms of increased risk for some side effects such as pancreatitis, I think it will be very important for practitioners to keep a close eye on the death risk regardless.
It’s very interesting that it’s similar to alcohol liver disease. With pancreatitis, not every single patient with alcohol addiction has pancreatitis. We don’t really fully understand why some people develop pancreatitis and some people do not. The point being that there are many patients with alcohol addiction who don’t have pancreatitis and may benefit from these medications if they work. Again, we have to prove that in patients.
On the other side, as we all know, pancreatitis is a potentially life-threatening condition for those people who either have it or are at risk for it. I think we have to be very careful before we consider giving them a GLP-1 RA.
One could argue that alcohol is the leading cause of mortality and morbidity in the world. For example, right now, alcohol is the leading cause of liver disease. It’s the main reason for liver transplantation in our country. Alcohol is affecting thousands of people in terms of death and emergency room visits.
You could argue that the downside is not treating these people and they die because of alcohol addiction. A GLP-1 RA is not going to be for everybody. I will remind everybody that (1) we do have FDA-approved medications for alcohol addiction; and (2) there are also other medications not approved by the FDA, but with a proven efficacy in some clinical trials — for example, topiramate and gabapentin — and they’ve been endorsed by the American Psychiatric Association.
There is also some evidence for another medication, baclofen, which has been endorsed by the American College of Gastroenterology for patients with alcohol addiction and liver disease.
The point I’m making is that it’s not that either we use the GLP-1 RAs or we have no other tools. We have other tools. I think we have to personalize the treatment based on the patient’s profile from a safety standpoint and from a phenotypic standpoint.
Dr. Jain: I love that thought. I think individualization is the key here.
We know that people with diabetes have a higher risk for pancreatitis by virtue of having diabetes. People with obesity also have a higher risk for pancreatitis by virtue of having obesity. These are the two conditions where we are using a large amount of GLP-1 RA therapy. Again, the idea is looking at the person in front of us and then deciding, based on their past medical history and their current risk, whether or not a medication is a right fit for them.
I think more individualization here will come as we start using these medications that might be having potential effects on different organ systems. You mentioned a little bit about the liver, so a thought came in my mind. We know that people with diabetes who have alcohol use disorder are at a higher risk for potential hypoglycemia. If they have events when they have increased consumption of alcohol, there can be more hypoglycemia.
We now could potentially be using semaglutide or other GLP-1 RA therapy for management of alcohol use disorder. In your own experience in the studies that you’ve done or the literature that’s out there, has that been associated with an even higher risk for hypoglycemia?
Dr. Leggio: It’s a wonderful question. I’m not aware of any formal and published report of that association. That said, your thinking from a physiopathologist standpoint makes total sense. I could not agree more. The fact that nothing has been published, at least to my knowledge, doesn’t mean that the death risk doesn’t exist. In fact, I agree with you that it does exist.
Alcohol use disorder is interesting and tricky clinically because chronically, alcohol addiction or alcohol use disorder is associated with an increased risk for diabetes. Acutely, as you point out; and this could be with or without alcohol use disorder. An episode of a high volume of binge drinking may lead to hypoglycemia.
This is one of the reasons why people may show up to the emergency room with intoxication, and one of the symptoms detected at the emergency room is that they also have hypoglycemia in addition to vomiting, nausea, and everything else that we see in patients with acute intoxication.
Similar to the discussion about pancreatitis, as we work on understanding the possible role of GLP-1 RA in patients with alcohol use disorder, we do have to keep a close eye on the risk for hypoglycemia. The short answer is that this is not well established, but based on the simple concept of “first, do no harm,” I think we need to track that very carefully.
In the ongoing clinical trial we’re doing in Maryland in my program at the NIH, we do just that. We are tracking glucose levels. Of course, patients come to clinic weekly, so unless they have symptoms, typically we don’t see anything at the time.
More important, we educate our patients when they go through the consent process. We tell them that this medication per se does not give hypoglycemia. In fact, we’re including people with diabetes, so for people on other medications like metformin, we explain to them that technically such a risk should not exist, but because you’re drinking alcohol in excessive amounts, you do have a potential higher risk. We just don’t know how significant that risk could be.
We do a large amount of education at baseline when they enroll in our study. We also educate our patients on how to recognize early on the potential risk for hypoglycemia, exactly for the reasons you said. We explain to them the unknown potential that the GLP-1 RAs and alcohol together may synergize and give hypoglycemia.
Dr. Jain: I don’t know if you got this feeling at the ADA conference, but I felt, when attending all these sessions, that it seems like GLP-1 RA is the gift that keeps giving. We see the effect on diabetes, obesity, metabolic-associated steatotic liver disease, possibly with Alzheimer’s, chronic obstructive pulmonary disease, and so many things.
Now, of course, there’s potential use in alcohol use disorder. Do you think that using GLP-1 RA therapy is ready for prime time? Do you think we are now ready to prescribe this in people with alcohol use disorder?
Dr. Leggio: I would say we’re not there yet. As I mentioned at the beginning, the evidence keeps on growing. It’s getting stronger and stronger because the positive data keep on coming up. We have data from animal models, including the different species, ranging from rodents to nonhuman primates. We have anecdotal evidence and machine-learning approaches using, for example, big data and social media data. Now we have pharmacoepidemiology data and some small, initial, but still good randomized clinical trials.
What we are missing is the final step of having a substantial number of prospective, double-blind, placebo-controlled clinical trials to really prove or disprove whether these medications work, and to also better understand which patients may respond to these medications.
The good news is that there are many ongoing clinical trials. We are conducting a clinical trial in Maryland at the NIH. Dr. Simmons is doing a clinical trial at Oklahoma State University. Dr. Christian Hendershot at UNC is conducting a study at Chapel Hill. Dr. Josh Gowin is doing a study in Colorado. Dr. Anders Fink-Jensen is doing a study in Denmark. The momentum is very high.
I’m only mentioning those people who are doing alcohol-semaglutide clinical trials. There are also people doing clinical trials on smoking, stimulants, and opioids. There are actually some very fresh, still unpublished data from Penn State that were presented publicly at conferences, showing how these drugs may reduce opioid craving, which is, of course, critically important, given that we’re in the middle of a fentanyl pandemic that is killing one person every 7 minutes, for example, in Baltimore. It’s very alarming and we need more treatments.
The bottom line is that it’s very promising, but we need to wait for these clinical trials to have a definitive answer. I would say that if you have a patient with diabetes, obesity, and also alcohol addiction, and they are on semaglutide or any other GLP-1 RA, and in addition to using the medication for diabetes and obesity, they also have a beneficial effect on their alcohol drinking, then that’s fantastic. At the end of the day, that’s the mission we all share: helping people.
If it’s someone without obesity and diabetes, personally, at this stage, I will go with other medications that either have FDA approval or at least very solid evidence of efficacy from RCTs rather than going with the GLP-1 RA, at least until I see more definitive data from randomized clinical trials.
There is a large amount of hope. We are hoping that these clinical trials will be positive. We are very enthusiastic and we’re also very thrilled to see that Novo Nordisk recently launched a gigantic multisite clinical trial with — I forgot how many sites, but it’s very large across Europe, America, and maybe other continents as well.
Their primary outcome is improvement in alcohol-related liver disease, but they’re also looking at alcohol drinking as a secondary outcome. That’s very important because, unlike in the diabetes field, in the addiction field, we do struggle to build partnership with the private sector because sometimes the addiction field is not seen as an appetitive field from pharma.
We all know that the best success in any medication development story is when you put academia, the government, and pharma together. Think about the COVID-19 vaccine development. That’s unfortunately the exception rather than rule in the addiction field.
With the company doing a large clinical trial in the alcohol field, although they focus more on the liver but they also looked at drinking, I really hope we’ll see more and more companies in the private sector take more and more interest in addiction. Also, I hope to see more and more partnership between the private sector, the government, and academia.
Dr. Jain: Such exciting times, indeed. We can’t wait enough for the results of these and many other trials to come out. Dr. Leggio, it was an absolute delight chatting with you today. Thank you so much for joining us from ADA 2024.
Akshay B. Jain, MD, Clinical Instructor, Department of Endocrinology, University of British Columbia; Endocrinologist, TLC Diabetes and Endocrinology, Vancouver, British Columbia, Canada, has disclosed the following relevant financial relationships: Serve(d) as a speaker or a member of a speakers bureau for: Abbott; Acerus; AstraZeneca; Amgen; Bausch Healthcare; Bayer; Boehringer Ingelheim; Care to Know; CCRN; Connected in Motion; CPD Network; Dexcom; Diabetes Canada; Eli Lilly; GSK; HLS Therapeutics; Janssen; Master Clinician Alliance; MDBriefcase; Merck; Medtronic; Moderna; Novartis; Novo Nordisk; Partners in Progressive Medical Education; Pfizer; Sanofi Aventis; Timed Right; WebMD. Received research grants/research support from: Abbott; Amgen; Novo Nordisk. Received consulting fees from: Abbott; Acerus; AstraZeneca; Amgen; Bausch Healthcare; Bayer; Boehringer Ingelheim; Dexcom; Eli Lilly; Gilead Sciences; GSK; HLS Therapeutics; Insulet; Janssen; Medtronic; Novo Nordisk; Partners in Progressive Medical Education; PocketPills; Roche; Sanofi Aventis; Takeda. Lorenzo Leggio, MD, PhD, Clinical Director, Deputy Scientific Director, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Baltimore, Maryland, has disclosed the following relevant financial relationships: Serve(d) as a US federal employee for: National Institutes of Health. He had received income in an amount equal to or greater than $250 from: UK Medical Council on Alcohol for his service as editor-in-chief for Alcohol and Alcoholism and received royalties from Rutledge as an editor for a textbook.
A version of this article first appeared on Medscape.com.
This transcript has been edited for clarity.
Akshay B. Jain, MD: Today we are very excited to have Dr. Leggio join us all the way from the National Institutes of Health (NIH). He is an addiction physician scientist in the intramural research program at NIH. Welcome, Dr. Leggio. Thanks for joining us.
Lorenzo Leggio, MD, PhD: Thank you so much.
Dr. Jain: We’ll get right into this. Your session was, in my mind, extremely informative. The session looked at glucagon-like peptide 1 receptor agonist (GLP-1 RA) therapy and its potential effects on mitigating alcohol misuse syndrome, so, reduction of alcohol addiction potentially.
We’ve seen in some previous clinical trials, including many from your group, that alcohol use is known to be reduced — the overall risk of incidence, as well as recurrence of alcohol use — in individuals who are on GLP-1 RA therapy.
Can you share more insights about the data already out there?
Dr. Leggio: At the preclinical level, we have a very robust line of studies, experiments, and publications looking at the effect of GLP-1 RAs, starting from exenatide up to, more recently, semaglutide. They show that these GLP-1 RAs do reduce alcohol drinking. They used different animal models of excessive alcohol drinking, using different species — for example, mice, rats, nonhuman primates — models that reflect the excessive alcohol drinking behavior that we see in patients, like physical alcohol dependence or binge-like alcohol drinking, and other behaviors in animal models that reflect the human condition.
In addition to that, we recently have seen an increase in human evidence that GLP-1 RAs may reduce alcohol drinking. For example, there is some anecdotal evidence and some analyses using social media showing that people on GLP-1 RAs report drinking less alcohol.
There are also some pharmacoepidemiology studies which are very intriguing and quite promising. In this case, people have been looking at electronic medical records; they have used the pharmacoepidemiology approaches to match patients on GLP-1 RAs because of diabetes or obesity, and have compared and matched to patients on different drugs as the controls.
A study was recently published Nature Communications by a group in Cleveland in collaboration with Dr. Nora Volkow from the National Institute on Drug Abuse. This study shows the association between being on a GLP-1 RA and the lower incidence of alcohol use disorder and lower drinking.
There is also some promise from prospective randomized clinical trials. In particular, there was one clinical trial from Denmark, a well-known and -conducted clinical trial where they looked at exenatide, and they didn’t see an effect of exenatide compared with placebo in the main analysis. But in a subanalysis, they did see that exenatide reduced alcohol drinking, but only in patients with alcohol use disorder and obesity.
This suggests that these medications may work for some patients and not for other patients. That’s fine, because just like in any other field in medicine, including diabetes, obesity, hypertension, Parkinson’s, and depression, not all medications work for everybody. If these medications will work for alcohol addiction, we do not expect that they will work for everybody.
One ongoing question in the field is to try to identify the phenotypes or the subgroup of people who may be more responsive to these medications.
Dr. Jain: This is such a fascinating field, and all these studies are coming out. In your review of all the literature so far, do you think this is dose dependent? Also, we see that, for instance, with certain individuals, when they take GLP-1 RA therapy, they might have a lot of gastrointestinal (GI) side effects. Recent studies have shown that the rate of these GI side effects does not necessarily correlate with the amount of weight loss. In the alcohol addiction field, do you think that the GI side effects, things like nausea, could also have a potential role in mitigating the alcohol addiction?
Dr. Leggio: This is a great question. They may play a role; they may contribute, too, but we don’t think that they are the driving mechanism of why people drink less, for at least a couple of reasons.
One is that, similar to the obesity field, the data we have so far don’t necessarily show a relationship between the GI side effects and the reduction in drinking. Plus, the reduction in drinking is likely to happen later when many GI side effects are gone or attenuated.
The second reason is from the neuroscience field. We are starting to better understand the mechanism at the brain level as to how these medications work. We don’t see that the nausea or, more generally, not feeling well — malaise, etc. — are driving mechanisms for how these medications work.
Again, it’s not to discount completely that the GI side effects may play a role, but I would say that, if anything, they may be more contributing to. And if they do, that will not be unique to this class of medication. For example, we have three medications approved by the US Food and Drug Administration (FDA) for alcohol use disorder.
One challenge we have in the addiction field is that many people don’t know that these medications exist — many primary care providers don’t know — and they are completely underutilized. Everybody here who is listening to us knows that roughly 85% of people with diabetes receive a medication for diabetes. For alcohol use disorder, the number is 2%. These are medications approved by the FDA.
One of them is naltrexone, which does give GI symptoms — in particular, nausea and vomiting. The other medication is acamprosate, which does give diarrhea.
You have medications approved for alcohol disorder where you do have some GI symptoms, but they are not the mechanism either for how these medications help people to curb craving and reduce alcohol drinking.
Dr. Jain: What about the dose-dependent action? Do you think that GLP-1 RAs, at a lower dose, may not have an effect on alcohol use disorder vs at a higher dose, or is everyone a little different?
Dr. Leggio: That’s a wonderful question. The short answer is, we don’t know, to be honest. Now, in some of the animal studies — my team has been in collaboration with other scientists in the NIH intramural research program, and also with scientists in academia, for example, at Scripps, UCLA — we see a dose response where the higher the dose, the higher the effect of the drug. In this case, semaglutide reduced binge drinking in a rat model of a physical alcohol dependence.
That said, I would be very cautious about claiming, based on the rodent data, that humans will have a dose response. It’s an open question. We really don’t know. Some of the pharmacoepidemiology data suggested that even lower doses — for example, using semaglutide for diabetes without going up to the obesity dose — may be just as effective as a higher dose in reducing the incidence of alcohol use disorder.
It’s important also to keep in mind that the pharmacoepidemiology data are always an association. Reduction in alcohol disorder is associated with the prescription GLP-1 RA, but they don’t really replace the more gold-standard, double-blind, placebo-controlled randomized clinical trial. Nonetheless, with the pharmacoepidemiology data, I think there is an argument to at least hypothesize that people may respond well, even to lower doses.
This also may be important from a safety standpoint.
Basically, we need to wait for results in the next years to come from randomized clinical trials to better unfold the question about doses. For example, just anecdotally, I will tell you that in the clinical trial we are conducting right now at the NIH Intramural Research Program, for which I’m the principal investigator (PI), we are going up to 2.4 mg — the highest dose of semaglutide.
We are collaborating with Kyle Simmons, PhD, from Oklahoma State University. Our two studies are not like a two-site clinical trial, but they are harmonized. In Dr. Simmons’ clinical trial, they’re going up to 1.0 mg. We are excited about this team approach because the trials are slightly different, but they’re harmonized to the point that, once the studies are done, we’ll be able to combine and compare data to better answer the question about dosing, and many other questions.
Dr. Jain: From a clinical perspective, we see that many people who are battling alcohol use disorder may not have obesity. They might actually be on the leaner side, and hence, we may not want to use a high dose of GLP-1 RA therapy. It’ll be very exciting to see when these results come out.
This brings me to the next question. I think everyone would love to know why this happens. Why is GLP-1 RA having this effect on alcohol use disorder? I know that your group has done many animal studies, as you pointed out, and one of the postulated theories was the effect on the GABA neurotransmission pathway.
Can you tell us more about what you feel is the underlying mechanism of action here?
Dr. Leggio: I will start by saying that we don’t fully know. There are many open questions. If I can sidetrack for one second: We come up with the idea that, first of all, alcohol use disorder and substance use disorder are addictive behaviors, addictive disorders. We define addiction as a brain disease.
Granted that addiction is a brain disease, it doesn’t mean that addiction works just in the brain in isolation. As we all know, the brain works in concert with the rest of the body. One specific approach my team has been taking is working on the analogy and the similarities between obesity and addiction to try to understand how the body-brain connection, such as the gut-brain-neuroendocrine pathway, may play a role in patients with addiction.
With that in mind, a large amount of work in my lab in the past 20 years — since I’ve been a PI — has been focused on studying this neuroendocrine pathways related to the gut-brain axis. For example, we have done work on insulin and leptin, primarily; we had done work on ghrelin, and since 2015 on the GLP-1 RAs.
With that in mind, the framework we are working on, which is also substantiated by many studies done by our team and other teams in the neuroscience field, kind of supports the idea that, similar to what we see in obesity, these medications may work by affecting what we call reward processing, or the seeking for addictive drugs, such as alcohol, and also the drugs such as the stimulants, opioids, nicotine, and so on.
The idea is that the mechanism is driven by the ability of the medication — semaglutide and all the GLP-1 RAs — to reduce the rewarding properties of alcohol and drugs. To maybe make the example more pragmatic, what does that mean? It means, for example, that a patient who typically has 10 drinks per day in the afternoon and night, while they are on the medication they may feel the lack of need to drink up to 10 to feel the same reward.
They may be able to stop after two or three drinks, which means a significant harm reduction and a beneficial outcome. This also brings us to another mechanism, which may be related to society. We don’t fully understand how much the society mechanism, including society mechanism related to GI motility, may also play a role.
With that said, we don’t think that the effect of the GLP-1 RAs is merely due to alcohol being a calorie-based nutrient because, in fact, we see alcohol as an addictive drug, not as a nutrient. Also, the GLP-1 RAs, at least in animal models, seem to work on other addictive drugs that don’t have calories, such as nicotine, and possibly with cannabis, opioids, and stimulants.
Then on the molecular level, our team recently showed, in collaboration with Dr. Marisa Roberto from Scripps in La Jolla, California, that semaglutide may in fact change the GABA transmission at the level of some brain regions, such as the amygdala and the prefrontal cortex. These are brain regions that are well-established hubs that play a role in the mechanism underlying addiction.
There are also some very exciting recent data showing how these medications may work not just on GABA or just on dopamine, which is the canonical way we conceive of reward processing, but by working on both by modulating GABA transmission — for example, at the ventral tegmental area and dopamine transmission at the nucleus accumbens.
Bottom line, if I summarize all of this, is that the mechanism is not fully understood, but there is definitely a contribution of this medication to effect and reward processing, possibly by altering the balance between GABA and dopamine. There are still some unknown questions, such as, are these mechanisms all brain driven or are they signaling from the periphery to the brain, or maybe both?
Also, as we all know, there are many differences across all these GLP-1 analogs in brain penetrance. Whether the drug needs to go to the brain to have an effect on alcohol drinking, cocaine seeking, or smoking is really an open question.
Dr. Jain: This is so thought-provoking. I guess the more we uncover, the more mesmerized we get with all the potential crosstalk. There is a large amount of overlap in the brain with each of these different things and how it all interplays with each other.
Speaking of interplay, I’m thinking about how many people prone to having alcohol use disorder can potentially develop complications, one of these being chronic pancreatitis. This is a well-known complication that can occur in people having alcohol addiction. Along that same line, we know that previous history of pancreatitis is considered a use-with-caution, or we don’t want to use GLP-1 RA therapy in people who have had pancreatitis.
Now it becomes this quagmire where people may have chronic pancreatitis, but we may want to consider GLP-1 RA therapy for management of alcohol use disorder. What are your thoughts about this, and the safety, potentially, in using it in these patients?
Dr. Leggio: This is another wonderful question. That’s definitely a top priority in our mind, to address these kinds of questions. For example, our RCT does have, as core primary outcomes, not only the efficacy defined as a reduction in alcohol drinking, but also safety.
The reason is exactly what you just explained. There are many unanswered questions, including whether giving a GLP-1 RA and alcohol together may have synergistic effects and increase the likelihood of having pancreatitis.
The good news is that, so far, based on the published literature, including the RCT done with exenatide in Denmark and published in 2022 and also the ongoing clinical trials — including my own clinical trial, but of course we are blind — pancreatitis has not been coming out as an adverse event.
However, it’s also true that it often happens in clinical medication development. Of course, we screen and select our population well. For example, we do exclude people who have a history of pancreatitis. We exclude people with high lipase or with any of the clinical symptomatology that makes us concerned about these people having pancreatitis.
As often happens when you move a medication from clinical trials to clinical practice, we still need to understand whether this medication works in patients. I’m just speculating, but even if the clinical trials do not raise red flags in terms of increased risk for some side effects such as pancreatitis, I think it will be very important for practitioners to keep a close eye on the death risk regardless.
It’s very interesting that it’s similar to alcohol liver disease. With pancreatitis, not every single patient with alcohol addiction has pancreatitis. We don’t really fully understand why some people develop pancreatitis and some people do not. The point being that there are many patients with alcohol addiction who don’t have pancreatitis and may benefit from these medications if they work. Again, we have to prove that in patients.
On the other side, as we all know, pancreatitis is a potentially life-threatening condition for those people who either have it or are at risk for it. I think we have to be very careful before we consider giving them a GLP-1 RA.
One could argue that alcohol is the leading cause of mortality and morbidity in the world. For example, right now, alcohol is the leading cause of liver disease. It’s the main reason for liver transplantation in our country. Alcohol is affecting thousands of people in terms of death and emergency room visits.
You could argue that the downside is not treating these people and they die because of alcohol addiction. A GLP-1 RA is not going to be for everybody. I will remind everybody that (1) we do have FDA-approved medications for alcohol addiction; and (2) there are also other medications not approved by the FDA, but with a proven efficacy in some clinical trials — for example, topiramate and gabapentin — and they’ve been endorsed by the American Psychiatric Association.
There is also some evidence for another medication, baclofen, which has been endorsed by the American College of Gastroenterology for patients with alcohol addiction and liver disease.
The point I’m making is that it’s not that either we use the GLP-1 RAs or we have no other tools. We have other tools. I think we have to personalize the treatment based on the patient’s profile from a safety standpoint and from a phenotypic standpoint.
Dr. Jain: I love that thought. I think individualization is the key here.
We know that people with diabetes have a higher risk for pancreatitis by virtue of having diabetes. People with obesity also have a higher risk for pancreatitis by virtue of having obesity. These are the two conditions where we are using a large amount of GLP-1 RA therapy. Again, the idea is looking at the person in front of us and then deciding, based on their past medical history and their current risk, whether or not a medication is a right fit for them.
I think more individualization here will come as we start using these medications that might be having potential effects on different organ systems. You mentioned a little bit about the liver, so a thought came in my mind. We know that people with diabetes who have alcohol use disorder are at a higher risk for potential hypoglycemia. If they have events when they have increased consumption of alcohol, there can be more hypoglycemia.
We now could potentially be using semaglutide or other GLP-1 RA therapy for management of alcohol use disorder. In your own experience in the studies that you’ve done or the literature that’s out there, has that been associated with an even higher risk for hypoglycemia?
Dr. Leggio: It’s a wonderful question. I’m not aware of any formal and published report of that association. That said, your thinking from a physiopathologist standpoint makes total sense. I could not agree more. The fact that nothing has been published, at least to my knowledge, doesn’t mean that the death risk doesn’t exist. In fact, I agree with you that it does exist.
Alcohol use disorder is interesting and tricky clinically because chronically, alcohol addiction or alcohol use disorder is associated with an increased risk for diabetes. Acutely, as you point out; and this could be with or without alcohol use disorder. An episode of a high volume of binge drinking may lead to hypoglycemia.
This is one of the reasons why people may show up to the emergency room with intoxication, and one of the symptoms detected at the emergency room is that they also have hypoglycemia in addition to vomiting, nausea, and everything else that we see in patients with acute intoxication.
Similar to the discussion about pancreatitis, as we work on understanding the possible role of GLP-1 RA in patients with alcohol use disorder, we do have to keep a close eye on the risk for hypoglycemia. The short answer is that this is not well established, but based on the simple concept of “first, do no harm,” I think we need to track that very carefully.
In the ongoing clinical trial we’re doing in Maryland in my program at the NIH, we do just that. We are tracking glucose levels. Of course, patients come to clinic weekly, so unless they have symptoms, typically we don’t see anything at the time.
More important, we educate our patients when they go through the consent process. We tell them that this medication per se does not give hypoglycemia. In fact, we’re including people with diabetes, so for people on other medications like metformin, we explain to them that technically such a risk should not exist, but because you’re drinking alcohol in excessive amounts, you do have a potential higher risk. We just don’t know how significant that risk could be.
We do a large amount of education at baseline when they enroll in our study. We also educate our patients on how to recognize early on the potential risk for hypoglycemia, exactly for the reasons you said. We explain to them the unknown potential that the GLP-1 RAs and alcohol together may synergize and give hypoglycemia.
Dr. Jain: I don’t know if you got this feeling at the ADA conference, but I felt, when attending all these sessions, that it seems like GLP-1 RA is the gift that keeps giving. We see the effect on diabetes, obesity, metabolic-associated steatotic liver disease, possibly with Alzheimer’s, chronic obstructive pulmonary disease, and so many things.
Now, of course, there’s potential use in alcohol use disorder. Do you think that using GLP-1 RA therapy is ready for prime time? Do you think we are now ready to prescribe this in people with alcohol use disorder?
Dr. Leggio: I would say we’re not there yet. As I mentioned at the beginning, the evidence keeps on growing. It’s getting stronger and stronger because the positive data keep on coming up. We have data from animal models, including the different species, ranging from rodents to nonhuman primates. We have anecdotal evidence and machine-learning approaches using, for example, big data and social media data. Now we have pharmacoepidemiology data and some small, initial, but still good randomized clinical trials.
What we are missing is the final step of having a substantial number of prospective, double-blind, placebo-controlled clinical trials to really prove or disprove whether these medications work, and to also better understand which patients may respond to these medications.
The good news is that there are many ongoing clinical trials. We are conducting a clinical trial in Maryland at the NIH. Dr. Simmons is doing a clinical trial at Oklahoma State University. Dr. Christian Hendershot at UNC is conducting a study at Chapel Hill. Dr. Josh Gowin is doing a study in Colorado. Dr. Anders Fink-Jensen is doing a study in Denmark. The momentum is very high.
I’m only mentioning those people who are doing alcohol-semaglutide clinical trials. There are also people doing clinical trials on smoking, stimulants, and opioids. There are actually some very fresh, still unpublished data from Penn State that were presented publicly at conferences, showing how these drugs may reduce opioid craving, which is, of course, critically important, given that we’re in the middle of a fentanyl pandemic that is killing one person every 7 minutes, for example, in Baltimore. It’s very alarming and we need more treatments.
The bottom line is that it’s very promising, but we need to wait for these clinical trials to have a definitive answer. I would say that if you have a patient with diabetes, obesity, and also alcohol addiction, and they are on semaglutide or any other GLP-1 RA, and in addition to using the medication for diabetes and obesity, they also have a beneficial effect on their alcohol drinking, then that’s fantastic. At the end of the day, that’s the mission we all share: helping people.
If it’s someone without obesity and diabetes, personally, at this stage, I will go with other medications that either have FDA approval or at least very solid evidence of efficacy from RCTs rather than going with the GLP-1 RA, at least until I see more definitive data from randomized clinical trials.
There is a large amount of hope. We are hoping that these clinical trials will be positive. We are very enthusiastic and we’re also very thrilled to see that Novo Nordisk recently launched a gigantic multisite clinical trial with — I forgot how many sites, but it’s very large across Europe, America, and maybe other continents as well.
Their primary outcome is improvement in alcohol-related liver disease, but they’re also looking at alcohol drinking as a secondary outcome. That’s very important because, unlike in the diabetes field, in the addiction field, we do struggle to build partnership with the private sector because sometimes the addiction field is not seen as an appetitive field from pharma.
We all know that the best success in any medication development story is when you put academia, the government, and pharma together. Think about the COVID-19 vaccine development. That’s unfortunately the exception rather than rule in the addiction field.
With the company doing a large clinical trial in the alcohol field, although they focus more on the liver but they also looked at drinking, I really hope we’ll see more and more companies in the private sector take more and more interest in addiction. Also, I hope to see more and more partnership between the private sector, the government, and academia.
Dr. Jain: Such exciting times, indeed. We can’t wait enough for the results of these and many other trials to come out. Dr. Leggio, it was an absolute delight chatting with you today. Thank you so much for joining us from ADA 2024.
Akshay B. Jain, MD, Clinical Instructor, Department of Endocrinology, University of British Columbia; Endocrinologist, TLC Diabetes and Endocrinology, Vancouver, British Columbia, Canada, has disclosed the following relevant financial relationships: Serve(d) as a speaker or a member of a speakers bureau for: Abbott; Acerus; AstraZeneca; Amgen; Bausch Healthcare; Bayer; Boehringer Ingelheim; Care to Know; CCRN; Connected in Motion; CPD Network; Dexcom; Diabetes Canada; Eli Lilly; GSK; HLS Therapeutics; Janssen; Master Clinician Alliance; MDBriefcase; Merck; Medtronic; Moderna; Novartis; Novo Nordisk; Partners in Progressive Medical Education; Pfizer; Sanofi Aventis; Timed Right; WebMD. Received research grants/research support from: Abbott; Amgen; Novo Nordisk. Received consulting fees from: Abbott; Acerus; AstraZeneca; Amgen; Bausch Healthcare; Bayer; Boehringer Ingelheim; Dexcom; Eli Lilly; Gilead Sciences; GSK; HLS Therapeutics; Insulet; Janssen; Medtronic; Novo Nordisk; Partners in Progressive Medical Education; PocketPills; Roche; Sanofi Aventis; Takeda. Lorenzo Leggio, MD, PhD, Clinical Director, Deputy Scientific Director, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Baltimore, Maryland, has disclosed the following relevant financial relationships: Serve(d) as a US federal employee for: National Institutes of Health. He had received income in an amount equal to or greater than $250 from: UK Medical Council on Alcohol for his service as editor-in-chief for Alcohol and Alcoholism and received royalties from Rutledge as an editor for a textbook.
A version of this article first appeared on Medscape.com.
FROM ADA 2024
Hormone Therapy Can Benefit Women into Their 80s
Hormone therapy (HT) can help women manage menopause symptoms into their 80s and the reasons are varied, according to a retrospective analysis being presented at the annual meeting of The Menopause Society.
“It’s important to know that this is a preselected group of women who had no contraindications to continuing their hormone therapy,” senior author Wendy Wolfman, MD, director of the Menopause Clinic and The Premature Ovarian Insufficiency Clinic at Mount Sinai Hospital in Toronto, Ontario, Canada, said in an interview. “They had the initiation of hormone therapy closer to menopause and carried on their hormones. We followed them for a long time and basically saw no real concerns about taking the hormones and the patients did very well. It’s important to emphasize this was not the new initiation of hormone therapy in elderly women.”
She said that, in her large tertiary referral center, “I still see patients who are referred who are told that they have to stop their hormones after 5 years based on a false assumption. Everybody ages at different rates and everybody has different risk factors.”
About 70%-80% of women experience menopause symptoms that restrict quality of life and productivity, the authors noted. HT has consistently been the most effective means for managing many of the side effects, especially hot flashes.
Hot flashes last on average 7-11 years. But they continue in up to 40% of women in their 60s and 10%-15% in their 70s, the authors wrote.
The analysis included more than 100 women in Canada older than 65 who continue to use HT and explored the motivations of the women to use them.
The average age of the women was 71 and nearly 8% were age 80 or older. The mean age for starting HT was 52 years and the women continued HT for an average 18 years, though 42% used it regularly for more than 20 years. Most of the women (nearly 88%) used a transdermal form of estrogen; only 12% used oral estrogen pills. Fewer than 5% of participants used synthetic progestins.
Controlling hot flashes was the No. 1 reason the women continued HT beyond age 65 (55%), followed by a desire for a better quality of life (29%), and to reduce chronic pain and arthritis symptoms (7%).
Some adverse effects were reported – postmenopausal bleeding was the most common – but no strokes, myocardial infarctions, or uterine cancers were documented.
More than one fourth (26.4%) of the women tried stopping HT once, but 87% reported that the return of hot flashes was the main reason to restart HT.
In addition, “many women choose to continue hormone therapy long term for relief of nonvasomotor symptoms, preservation of bone density, and a desire to benefit from potential long-term cardiovascular protection,” said Lauren F. Streicher, MD, Professor of Obstetrics and Gynecology at Feinberg School of Medicine at Northwestern University in Chicago, who was not part of the research.
In 2022, The Menopause Society position statement on hormone therapy acknowledged that, on an individual basis, it is appropriate for women to continue hormone therapy long term with counseling on benefits and risks.
“However, few studies have evaluated the outcomes of using hormone therapy for more than 10 years, and individual motivation for doing so,” Dr. Streicher said. She pointed to a study that analyzed the insurance records of more than 10 million women who continued their HT past the age of 65 and reassuringly found that there were significant risk reductions in all-cause mortality, breast cancer, lung cancer, colorectal cancer, heart failure, venous thromboembolism, atrial fibrillation, acute myocardial infarction, and dementia. In that study, however, the reasons women chose to continue hormone therapy were not specified.
“In this retrospective Canadian study,” she noted, “the outcomes were again reassuring, with no increase in strokes, myocardial infarctions, or uterine cancers. The reasons cited for continuing hormone therapy were not just to treat ongoing vasomotor symptoms, but also other menopause symptoms such as musculoskeletal aches and pains, and overall quality of life.
Dr. Streicher said that, while long-term longitudinal studies are needed to make definitive recommendations, “It is reassuring that women who choose to extend hormone therapy can safely do so. It is irresponsible, cruel, and nonsensical to continue to make blanket statements that hormone therapy should be discontinued based on age or years of use and commit women to enduring symptoms and depriving them of possible long-term benefits.”
Dr. Streicher gives lectures for Midi Health and owns Sermonix stock. Dr. Wolfman has been on the advisory boards for many pharmaceutical companies. She is the past president of the Canadian Menopause Society and is on the board of the International Menopause Society.
Hormone therapy (HT) can help women manage menopause symptoms into their 80s and the reasons are varied, according to a retrospective analysis being presented at the annual meeting of The Menopause Society.
“It’s important to know that this is a preselected group of women who had no contraindications to continuing their hormone therapy,” senior author Wendy Wolfman, MD, director of the Menopause Clinic and The Premature Ovarian Insufficiency Clinic at Mount Sinai Hospital in Toronto, Ontario, Canada, said in an interview. “They had the initiation of hormone therapy closer to menopause and carried on their hormones. We followed them for a long time and basically saw no real concerns about taking the hormones and the patients did very well. It’s important to emphasize this was not the new initiation of hormone therapy in elderly women.”
She said that, in her large tertiary referral center, “I still see patients who are referred who are told that they have to stop their hormones after 5 years based on a false assumption. Everybody ages at different rates and everybody has different risk factors.”
About 70%-80% of women experience menopause symptoms that restrict quality of life and productivity, the authors noted. HT has consistently been the most effective means for managing many of the side effects, especially hot flashes.
Hot flashes last on average 7-11 years. But they continue in up to 40% of women in their 60s and 10%-15% in their 70s, the authors wrote.
The analysis included more than 100 women in Canada older than 65 who continue to use HT and explored the motivations of the women to use them.
The average age of the women was 71 and nearly 8% were age 80 or older. The mean age for starting HT was 52 years and the women continued HT for an average 18 years, though 42% used it regularly for more than 20 years. Most of the women (nearly 88%) used a transdermal form of estrogen; only 12% used oral estrogen pills. Fewer than 5% of participants used synthetic progestins.
Controlling hot flashes was the No. 1 reason the women continued HT beyond age 65 (55%), followed by a desire for a better quality of life (29%), and to reduce chronic pain and arthritis symptoms (7%).
Some adverse effects were reported – postmenopausal bleeding was the most common – but no strokes, myocardial infarctions, or uterine cancers were documented.
More than one fourth (26.4%) of the women tried stopping HT once, but 87% reported that the return of hot flashes was the main reason to restart HT.
In addition, “many women choose to continue hormone therapy long term for relief of nonvasomotor symptoms, preservation of bone density, and a desire to benefit from potential long-term cardiovascular protection,” said Lauren F. Streicher, MD, Professor of Obstetrics and Gynecology at Feinberg School of Medicine at Northwestern University in Chicago, who was not part of the research.
In 2022, The Menopause Society position statement on hormone therapy acknowledged that, on an individual basis, it is appropriate for women to continue hormone therapy long term with counseling on benefits and risks.
“However, few studies have evaluated the outcomes of using hormone therapy for more than 10 years, and individual motivation for doing so,” Dr. Streicher said. She pointed to a study that analyzed the insurance records of more than 10 million women who continued their HT past the age of 65 and reassuringly found that there were significant risk reductions in all-cause mortality, breast cancer, lung cancer, colorectal cancer, heart failure, venous thromboembolism, atrial fibrillation, acute myocardial infarction, and dementia. In that study, however, the reasons women chose to continue hormone therapy were not specified.
“In this retrospective Canadian study,” she noted, “the outcomes were again reassuring, with no increase in strokes, myocardial infarctions, or uterine cancers. The reasons cited for continuing hormone therapy were not just to treat ongoing vasomotor symptoms, but also other menopause symptoms such as musculoskeletal aches and pains, and overall quality of life.
Dr. Streicher said that, while long-term longitudinal studies are needed to make definitive recommendations, “It is reassuring that women who choose to extend hormone therapy can safely do so. It is irresponsible, cruel, and nonsensical to continue to make blanket statements that hormone therapy should be discontinued based on age or years of use and commit women to enduring symptoms and depriving them of possible long-term benefits.”
Dr. Streicher gives lectures for Midi Health and owns Sermonix stock. Dr. Wolfman has been on the advisory boards for many pharmaceutical companies. She is the past president of the Canadian Menopause Society and is on the board of the International Menopause Society.
Hormone therapy (HT) can help women manage menopause symptoms into their 80s and the reasons are varied, according to a retrospective analysis being presented at the annual meeting of The Menopause Society.
“It’s important to know that this is a preselected group of women who had no contraindications to continuing their hormone therapy,” senior author Wendy Wolfman, MD, director of the Menopause Clinic and The Premature Ovarian Insufficiency Clinic at Mount Sinai Hospital in Toronto, Ontario, Canada, said in an interview. “They had the initiation of hormone therapy closer to menopause and carried on their hormones. We followed them for a long time and basically saw no real concerns about taking the hormones and the patients did very well. It’s important to emphasize this was not the new initiation of hormone therapy in elderly women.”
She said that, in her large tertiary referral center, “I still see patients who are referred who are told that they have to stop their hormones after 5 years based on a false assumption. Everybody ages at different rates and everybody has different risk factors.”
About 70%-80% of women experience menopause symptoms that restrict quality of life and productivity, the authors noted. HT has consistently been the most effective means for managing many of the side effects, especially hot flashes.
Hot flashes last on average 7-11 years. But they continue in up to 40% of women in their 60s and 10%-15% in their 70s, the authors wrote.
The analysis included more than 100 women in Canada older than 65 who continue to use HT and explored the motivations of the women to use them.
The average age of the women was 71 and nearly 8% were age 80 or older. The mean age for starting HT was 52 years and the women continued HT for an average 18 years, though 42% used it regularly for more than 20 years. Most of the women (nearly 88%) used a transdermal form of estrogen; only 12% used oral estrogen pills. Fewer than 5% of participants used synthetic progestins.
Controlling hot flashes was the No. 1 reason the women continued HT beyond age 65 (55%), followed by a desire for a better quality of life (29%), and to reduce chronic pain and arthritis symptoms (7%).
Some adverse effects were reported – postmenopausal bleeding was the most common – but no strokes, myocardial infarctions, or uterine cancers were documented.
More than one fourth (26.4%) of the women tried stopping HT once, but 87% reported that the return of hot flashes was the main reason to restart HT.
In addition, “many women choose to continue hormone therapy long term for relief of nonvasomotor symptoms, preservation of bone density, and a desire to benefit from potential long-term cardiovascular protection,” said Lauren F. Streicher, MD, Professor of Obstetrics and Gynecology at Feinberg School of Medicine at Northwestern University in Chicago, who was not part of the research.
In 2022, The Menopause Society position statement on hormone therapy acknowledged that, on an individual basis, it is appropriate for women to continue hormone therapy long term with counseling on benefits and risks.
“However, few studies have evaluated the outcomes of using hormone therapy for more than 10 years, and individual motivation for doing so,” Dr. Streicher said. She pointed to a study that analyzed the insurance records of more than 10 million women who continued their HT past the age of 65 and reassuringly found that there were significant risk reductions in all-cause mortality, breast cancer, lung cancer, colorectal cancer, heart failure, venous thromboembolism, atrial fibrillation, acute myocardial infarction, and dementia. In that study, however, the reasons women chose to continue hormone therapy were not specified.
“In this retrospective Canadian study,” she noted, “the outcomes were again reassuring, with no increase in strokes, myocardial infarctions, or uterine cancers. The reasons cited for continuing hormone therapy were not just to treat ongoing vasomotor symptoms, but also other menopause symptoms such as musculoskeletal aches and pains, and overall quality of life.
Dr. Streicher said that, while long-term longitudinal studies are needed to make definitive recommendations, “It is reassuring that women who choose to extend hormone therapy can safely do so. It is irresponsible, cruel, and nonsensical to continue to make blanket statements that hormone therapy should be discontinued based on age or years of use and commit women to enduring symptoms and depriving them of possible long-term benefits.”
Dr. Streicher gives lectures for Midi Health and owns Sermonix stock. Dr. Wolfman has been on the advisory boards for many pharmaceutical companies. She is the past president of the Canadian Menopause Society and is on the board of the International Menopause Society.
FROM THE MENOPAUSE SOCIETY 2024
Setbacks Identified After Stopping Beta-Blockers
LONDON — It may not be advisable for patients with a history of myocardial infarction and preserved left ventricular function to discontinue long-term beta-blocker therapy, warn investigators.
In the randomized ABYSS trial, although there was no difference in death, MI, or stroke between patients who discontinued and those who continued taking beta-blockers, those who stopped taking the drugs had a higher rate of cardiovascular hospitalization.
Discontinuation was also associated with an increase in blood pressure and heart rate, without any improvement in quality of life.
The results, which were simultaneously published online in The New England Journal of Medicine, call into question current guidelines, which suggest that beta-blockers may be discontinued after 1 year in certain patient groups.
Beta-blockers have long been considered the standard of care for patients after MI, but trials showing the benefit of these drugs were conducted before the modern era of myocardial reperfusion and pharmacotherapy, which have led to sharp decreases in the risk for heart failure and for death after MI, Dr. Silvain explained.
This has led to questions about the add-on benefits of lifelong beta-blocker treatment for patients with MI and a preserved left ventricular ejection fraction and no other primary indication for beta-blocker therapy.
The ABYSS Trial
To explore this issue, the open-label, non-inferiority ABYSS trial randomly assigned 3698 patients with a history of MI to the discontinuation or continuation of beta-blocker treatment. All study participants had a left ventricular ejection fraction of at least 40%, were receiving long-term beta-blocker treatment, and had experienced no cardiovascular event in the previous 6 months.
At a median follow-up of 3 years, the primary endpoint — a composite of death, MI, stroke, and hospitalization for cardiovascular reasons — occurred more often in the discontinuation group than in the continuation group (23.8% vs 21.1%; hazard ratio, 1.16; 95% CI, 1.01-1.33). This did not meet the criteria for non-inferiority of discontinuation, compared with continuation, of beta-blocker therapy (P for non-inferiority = .44).
The difference in event rates between the two groups was driven by cardiovascular hospitalizations, which occurred more often in the discontinuation group than in the continuation group (18.9% vs 16.6%).
Other key results showed that there was no difference in quality of life between the two groups.
However, 6 months after randomization, there were increases in blood pressure and heart rate in the discontinuation group. Systolic blood pressure increased by 3.7 mm Hg and diastolic blood pressure increased by 3.9 mm Hg. Resting heart rate increased by 9.8 beats per minute.
“We were not able to show the non-inferiority of stopping beta-blockers in terms of cardiovascular events, [but we] showed a safety signal with this strategy of an increase in blood pressure and heart rate, with no improvement in quality of life,” Dr. Sylvain said.
“While recent guidelines suggest it may be reasonable to stop beta-blockers in this population, after these results, I will not be stopping these drugs if they are being well tolerated,” he said.
Sylvain said he was surprised that there was not an improvement in quality of life in the group that discontinued beta-blockers. “We are always told that beta-blockers have many side effects, so we expected to see an improvement in quality of life in the patients who stopped these drugs.”
One possible reason for the lack of improvement in quality of life is that the trial participants had been taking beta-blockers for several years. “We may have, therefore, selected patients who tolerate these drugs quite well. Those who had tolerance issues had probably already stopped taking them,” he explained.
In addition, the patient population had relatively high quality-of-life scores at baseline. “They were well treated and the therapies they were taking were well tolerated, so maybe it is difficult to improve quality of life further,” he said.
The REDUCE-AMI Trial
The ABYSS results appear at first to differ from results from the recent REDUCE-AMI trial, which failed to show the superiority of beta-blocker therapy, compared with no beta-blocker therapy, in acute MI patients with preserved ejection fraction.
But the REDUCE-AMI primary endpoint was a composite of death from any cause or new myocardial infarction; it did not include cardiovascular hospitalization, which was the main driver of the difference in outcomes in the ABYSS study, Dr. Sylvain pointed out.
“We showed an increase in coronary cases of hospitalization with stopping beta-blockers, and you have to remember that beta-blockers were developed to reduce coronary disease,” he said.
‘Slightly Inconclusive’
Jane Armitage, MBBS, University of Oxford, England, the ABYSS discussant for the ESC HOTLINE session, pointed out some limitations of the study, which led her to report that the result was “slightly inconclusive.”
The open-label design may have allowed some bias regarding the cardiovascular hospitalization endpoint, she said.
“The decision whether to admit a patient to [the] hospital is somewhat subjective and could be influenced by a physician’s knowledge of treatment allocation. That is why, ideally, we prefer blinded trials. I think there are questions there,” she explained.
She also questioned whether the non-inferiority margin could have been increased, given the higher-than-expected event rate.
More data on this issue will come from several trials that are currently ongoing, Dr. Armitage said.
The ABYSS and REDUCE-AMI trials together suggest that it is safe, with respect to serious cardiac events, to stop beta-blocker treatment in MI patients with preserved ejection fraction, writes Tomas Jernberg, MD, PhD, from the Karolinska Institute in Stockholm, Sweden, in an accompanying editorial.
However, “because of the anti-ischemic effects of beta-blockers, an interruption may increase the risk of recurrent angina and the need for rehospitalization,” he adds.
“It is prudent to wait for the results of additional ongoing trials of beta-blockers involving patients with MI and a preserved left ventricular ejection fraction before definitively updating guidelines,” Dr. Jernberg concludes.
The ABYSS trial was funded by the French Ministry of Health and the ACTION Study Group. Dr. Sylvain, Dr. Armitage, and Dr. Jernberg report no relevant financial relationships.
A version of this article appeared on Medscape.com.
LONDON — It may not be advisable for patients with a history of myocardial infarction and preserved left ventricular function to discontinue long-term beta-blocker therapy, warn investigators.
In the randomized ABYSS trial, although there was no difference in death, MI, or stroke between patients who discontinued and those who continued taking beta-blockers, those who stopped taking the drugs had a higher rate of cardiovascular hospitalization.
Discontinuation was also associated with an increase in blood pressure and heart rate, without any improvement in quality of life.
The results, which were simultaneously published online in The New England Journal of Medicine, call into question current guidelines, which suggest that beta-blockers may be discontinued after 1 year in certain patient groups.
Beta-blockers have long been considered the standard of care for patients after MI, but trials showing the benefit of these drugs were conducted before the modern era of myocardial reperfusion and pharmacotherapy, which have led to sharp decreases in the risk for heart failure and for death after MI, Dr. Silvain explained.
This has led to questions about the add-on benefits of lifelong beta-blocker treatment for patients with MI and a preserved left ventricular ejection fraction and no other primary indication for beta-blocker therapy.
The ABYSS Trial
To explore this issue, the open-label, non-inferiority ABYSS trial randomly assigned 3698 patients with a history of MI to the discontinuation or continuation of beta-blocker treatment. All study participants had a left ventricular ejection fraction of at least 40%, were receiving long-term beta-blocker treatment, and had experienced no cardiovascular event in the previous 6 months.
At a median follow-up of 3 years, the primary endpoint — a composite of death, MI, stroke, and hospitalization for cardiovascular reasons — occurred more often in the discontinuation group than in the continuation group (23.8% vs 21.1%; hazard ratio, 1.16; 95% CI, 1.01-1.33). This did not meet the criteria for non-inferiority of discontinuation, compared with continuation, of beta-blocker therapy (P for non-inferiority = .44).
The difference in event rates between the two groups was driven by cardiovascular hospitalizations, which occurred more often in the discontinuation group than in the continuation group (18.9% vs 16.6%).
Other key results showed that there was no difference in quality of life between the two groups.
However, 6 months after randomization, there were increases in blood pressure and heart rate in the discontinuation group. Systolic blood pressure increased by 3.7 mm Hg and diastolic blood pressure increased by 3.9 mm Hg. Resting heart rate increased by 9.8 beats per minute.
“We were not able to show the non-inferiority of stopping beta-blockers in terms of cardiovascular events, [but we] showed a safety signal with this strategy of an increase in blood pressure and heart rate, with no improvement in quality of life,” Dr. Sylvain said.
“While recent guidelines suggest it may be reasonable to stop beta-blockers in this population, after these results, I will not be stopping these drugs if they are being well tolerated,” he said.
Sylvain said he was surprised that there was not an improvement in quality of life in the group that discontinued beta-blockers. “We are always told that beta-blockers have many side effects, so we expected to see an improvement in quality of life in the patients who stopped these drugs.”
One possible reason for the lack of improvement in quality of life is that the trial participants had been taking beta-blockers for several years. “We may have, therefore, selected patients who tolerate these drugs quite well. Those who had tolerance issues had probably already stopped taking them,” he explained.
In addition, the patient population had relatively high quality-of-life scores at baseline. “They were well treated and the therapies they were taking were well tolerated, so maybe it is difficult to improve quality of life further,” he said.
The REDUCE-AMI Trial
The ABYSS results appear at first to differ from results from the recent REDUCE-AMI trial, which failed to show the superiority of beta-blocker therapy, compared with no beta-blocker therapy, in acute MI patients with preserved ejection fraction.
But the REDUCE-AMI primary endpoint was a composite of death from any cause or new myocardial infarction; it did not include cardiovascular hospitalization, which was the main driver of the difference in outcomes in the ABYSS study, Dr. Sylvain pointed out.
“We showed an increase in coronary cases of hospitalization with stopping beta-blockers, and you have to remember that beta-blockers were developed to reduce coronary disease,” he said.
‘Slightly Inconclusive’
Jane Armitage, MBBS, University of Oxford, England, the ABYSS discussant for the ESC HOTLINE session, pointed out some limitations of the study, which led her to report that the result was “slightly inconclusive.”
The open-label design may have allowed some bias regarding the cardiovascular hospitalization endpoint, she said.
“The decision whether to admit a patient to [the] hospital is somewhat subjective and could be influenced by a physician’s knowledge of treatment allocation. That is why, ideally, we prefer blinded trials. I think there are questions there,” she explained.
She also questioned whether the non-inferiority margin could have been increased, given the higher-than-expected event rate.
More data on this issue will come from several trials that are currently ongoing, Dr. Armitage said.
The ABYSS and REDUCE-AMI trials together suggest that it is safe, with respect to serious cardiac events, to stop beta-blocker treatment in MI patients with preserved ejection fraction, writes Tomas Jernberg, MD, PhD, from the Karolinska Institute in Stockholm, Sweden, in an accompanying editorial.
However, “because of the anti-ischemic effects of beta-blockers, an interruption may increase the risk of recurrent angina and the need for rehospitalization,” he adds.
“It is prudent to wait for the results of additional ongoing trials of beta-blockers involving patients with MI and a preserved left ventricular ejection fraction before definitively updating guidelines,” Dr. Jernberg concludes.
The ABYSS trial was funded by the French Ministry of Health and the ACTION Study Group. Dr. Sylvain, Dr. Armitage, and Dr. Jernberg report no relevant financial relationships.
A version of this article appeared on Medscape.com.
LONDON — It may not be advisable for patients with a history of myocardial infarction and preserved left ventricular function to discontinue long-term beta-blocker therapy, warn investigators.
In the randomized ABYSS trial, although there was no difference in death, MI, or stroke between patients who discontinued and those who continued taking beta-blockers, those who stopped taking the drugs had a higher rate of cardiovascular hospitalization.
Discontinuation was also associated with an increase in blood pressure and heart rate, without any improvement in quality of life.
The results, which were simultaneously published online in The New England Journal of Medicine, call into question current guidelines, which suggest that beta-blockers may be discontinued after 1 year in certain patient groups.
Beta-blockers have long been considered the standard of care for patients after MI, but trials showing the benefit of these drugs were conducted before the modern era of myocardial reperfusion and pharmacotherapy, which have led to sharp decreases in the risk for heart failure and for death after MI, Dr. Silvain explained.
This has led to questions about the add-on benefits of lifelong beta-blocker treatment for patients with MI and a preserved left ventricular ejection fraction and no other primary indication for beta-blocker therapy.
The ABYSS Trial
To explore this issue, the open-label, non-inferiority ABYSS trial randomly assigned 3698 patients with a history of MI to the discontinuation or continuation of beta-blocker treatment. All study participants had a left ventricular ejection fraction of at least 40%, were receiving long-term beta-blocker treatment, and had experienced no cardiovascular event in the previous 6 months.
At a median follow-up of 3 years, the primary endpoint — a composite of death, MI, stroke, and hospitalization for cardiovascular reasons — occurred more often in the discontinuation group than in the continuation group (23.8% vs 21.1%; hazard ratio, 1.16; 95% CI, 1.01-1.33). This did not meet the criteria for non-inferiority of discontinuation, compared with continuation, of beta-blocker therapy (P for non-inferiority = .44).
The difference in event rates between the two groups was driven by cardiovascular hospitalizations, which occurred more often in the discontinuation group than in the continuation group (18.9% vs 16.6%).
Other key results showed that there was no difference in quality of life between the two groups.
However, 6 months after randomization, there were increases in blood pressure and heart rate in the discontinuation group. Systolic blood pressure increased by 3.7 mm Hg and diastolic blood pressure increased by 3.9 mm Hg. Resting heart rate increased by 9.8 beats per minute.
“We were not able to show the non-inferiority of stopping beta-blockers in terms of cardiovascular events, [but we] showed a safety signal with this strategy of an increase in blood pressure and heart rate, with no improvement in quality of life,” Dr. Sylvain said.
“While recent guidelines suggest it may be reasonable to stop beta-blockers in this population, after these results, I will not be stopping these drugs if they are being well tolerated,” he said.
Sylvain said he was surprised that there was not an improvement in quality of life in the group that discontinued beta-blockers. “We are always told that beta-blockers have many side effects, so we expected to see an improvement in quality of life in the patients who stopped these drugs.”
One possible reason for the lack of improvement in quality of life is that the trial participants had been taking beta-blockers for several years. “We may have, therefore, selected patients who tolerate these drugs quite well. Those who had tolerance issues had probably already stopped taking them,” he explained.
In addition, the patient population had relatively high quality-of-life scores at baseline. “They were well treated and the therapies they were taking were well tolerated, so maybe it is difficult to improve quality of life further,” he said.
The REDUCE-AMI Trial
The ABYSS results appear at first to differ from results from the recent REDUCE-AMI trial, which failed to show the superiority of beta-blocker therapy, compared with no beta-blocker therapy, in acute MI patients with preserved ejection fraction.
But the REDUCE-AMI primary endpoint was a composite of death from any cause or new myocardial infarction; it did not include cardiovascular hospitalization, which was the main driver of the difference in outcomes in the ABYSS study, Dr. Sylvain pointed out.
“We showed an increase in coronary cases of hospitalization with stopping beta-blockers, and you have to remember that beta-blockers were developed to reduce coronary disease,” he said.
‘Slightly Inconclusive’
Jane Armitage, MBBS, University of Oxford, England, the ABYSS discussant for the ESC HOTLINE session, pointed out some limitations of the study, which led her to report that the result was “slightly inconclusive.”
The open-label design may have allowed some bias regarding the cardiovascular hospitalization endpoint, she said.
“The decision whether to admit a patient to [the] hospital is somewhat subjective and could be influenced by a physician’s knowledge of treatment allocation. That is why, ideally, we prefer blinded trials. I think there are questions there,” she explained.
She also questioned whether the non-inferiority margin could have been increased, given the higher-than-expected event rate.
More data on this issue will come from several trials that are currently ongoing, Dr. Armitage said.
The ABYSS and REDUCE-AMI trials together suggest that it is safe, with respect to serious cardiac events, to stop beta-blocker treatment in MI patients with preserved ejection fraction, writes Tomas Jernberg, MD, PhD, from the Karolinska Institute in Stockholm, Sweden, in an accompanying editorial.
However, “because of the anti-ischemic effects of beta-blockers, an interruption may increase the risk of recurrent angina and the need for rehospitalization,” he adds.
“It is prudent to wait for the results of additional ongoing trials of beta-blockers involving patients with MI and a preserved left ventricular ejection fraction before definitively updating guidelines,” Dr. Jernberg concludes.
The ABYSS trial was funded by the French Ministry of Health and the ACTION Study Group. Dr. Sylvain, Dr. Armitage, and Dr. Jernberg report no relevant financial relationships.
A version of this article appeared on Medscape.com.
High-Dose Psilocybin Shows Promising Results for Depression
TOPLINE:
, a new meta-analysis suggests.
METHODOLOGY:
- Researchers conducted a network meta-analysis to evaluate the comparative effectiveness of oral monotherapy with psychedelics versus escitalopram in patients with clinically diagnosed depression.
- The meta-analysis included 811 participants (mean age, 42.49 years; 54.2% women) with clinically diagnosed depression across 15 psychedelic trials and 1968 participants (mean age, 39.35 years; 62.5% women) across five escitalopram trials.
- Trials evaluated oral monotherapy with psychedelics (psilocybin, lysergic acid diethylamide, 3,4-methylenedioxymethamphetamine [MDMA], and ayahuasca), fixed-dose escitalopram (up to 20 mg/d) versus placebo, and psychedelic versus escitalopram monotherapy.
- The primary outcome was a change in depressive symptoms from baseline.
TAKEAWAY:
- Placebo responses in antidepressant trials (mean difference, 3.79; 95% CI, 0.77-6.80) and extremely low-dose psilocybin (mean difference, 3.96; 95% CI, 0.61-7.17) were better than those in psychedelic trials.
- High-dose psilocybin (20 mg or more) performed better than placebo in the antidepressant trials (mean difference, > 3). However, when comparing high-dose psilocybin with the placebo used in antidepressant trials, the effect size was smaller. The standardized mean difference dropped from 0.88 to 0.31, indicating that the effect of high-dose psilocybin was similar to that of current antidepressants.
- High-dose psilocybin was associated with a greater response than escitalopram at 10 mg (4.66; 95% CI, 1.36-7.74) and 20 mg (4.69; 95% CI, 1.64-7.54).
- No interventions were associated with an increased risk for all-cause discontinuation or severe adverse events.
IN PRACTICE:
“Taken together, our study findings suggest that among psychedelic treatments, high-dose psilocybin is more likely to reach the minimal important difference for depressive symptoms in studies with adequate blinding design, while the effect size of psilocybin was similar to that of current antidepressant drugs, showing a mean standardized mean difference of 0.3,” the authors wrote.
SOURCE:
The study was led by Tien-Wei Hsu, MD, I-Shou University and Kaohsiung Medical University, Kaohsiung City, Taiwan. It was published online in The BMJ.
LIMITATIONS:
The study did not assess long-term effects of the interventions. Participants in the MDMA trials were primarily diagnosed with posttraumatic stress disorder, which may not be representative of the general population with depressive symptoms. Moreover, the sample size of the psychedelic trials was small. Using extremely low-dose psychedelics as a reference group may have eliminated some pharmacologic effects as these doses cannot be considered a placebo.
DISCLOSURES:
The study was supported by grants from the National Science and Technology Council. The authors declared no financial relationships with any organizations outside the submitted work in the past 3 years. Full disclosures are available in the original article.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.
TOPLINE:
, a new meta-analysis suggests.
METHODOLOGY:
- Researchers conducted a network meta-analysis to evaluate the comparative effectiveness of oral monotherapy with psychedelics versus escitalopram in patients with clinically diagnosed depression.
- The meta-analysis included 811 participants (mean age, 42.49 years; 54.2% women) with clinically diagnosed depression across 15 psychedelic trials and 1968 participants (mean age, 39.35 years; 62.5% women) across five escitalopram trials.
- Trials evaluated oral monotherapy with psychedelics (psilocybin, lysergic acid diethylamide, 3,4-methylenedioxymethamphetamine [MDMA], and ayahuasca), fixed-dose escitalopram (up to 20 mg/d) versus placebo, and psychedelic versus escitalopram monotherapy.
- The primary outcome was a change in depressive symptoms from baseline.
TAKEAWAY:
- Placebo responses in antidepressant trials (mean difference, 3.79; 95% CI, 0.77-6.80) and extremely low-dose psilocybin (mean difference, 3.96; 95% CI, 0.61-7.17) were better than those in psychedelic trials.
- High-dose psilocybin (20 mg or more) performed better than placebo in the antidepressant trials (mean difference, > 3). However, when comparing high-dose psilocybin with the placebo used in antidepressant trials, the effect size was smaller. The standardized mean difference dropped from 0.88 to 0.31, indicating that the effect of high-dose psilocybin was similar to that of current antidepressants.
- High-dose psilocybin was associated with a greater response than escitalopram at 10 mg (4.66; 95% CI, 1.36-7.74) and 20 mg (4.69; 95% CI, 1.64-7.54).
- No interventions were associated with an increased risk for all-cause discontinuation or severe adverse events.
IN PRACTICE:
“Taken together, our study findings suggest that among psychedelic treatments, high-dose psilocybin is more likely to reach the minimal important difference for depressive symptoms in studies with adequate blinding design, while the effect size of psilocybin was similar to that of current antidepressant drugs, showing a mean standardized mean difference of 0.3,” the authors wrote.
SOURCE:
The study was led by Tien-Wei Hsu, MD, I-Shou University and Kaohsiung Medical University, Kaohsiung City, Taiwan. It was published online in The BMJ.
LIMITATIONS:
The study did not assess long-term effects of the interventions. Participants in the MDMA trials were primarily diagnosed with posttraumatic stress disorder, which may not be representative of the general population with depressive symptoms. Moreover, the sample size of the psychedelic trials was small. Using extremely low-dose psychedelics as a reference group may have eliminated some pharmacologic effects as these doses cannot be considered a placebo.
DISCLOSURES:
The study was supported by grants from the National Science and Technology Council. The authors declared no financial relationships with any organizations outside the submitted work in the past 3 years. Full disclosures are available in the original article.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.
TOPLINE:
, a new meta-analysis suggests.
METHODOLOGY:
- Researchers conducted a network meta-analysis to evaluate the comparative effectiveness of oral monotherapy with psychedelics versus escitalopram in patients with clinically diagnosed depression.
- The meta-analysis included 811 participants (mean age, 42.49 years; 54.2% women) with clinically diagnosed depression across 15 psychedelic trials and 1968 participants (mean age, 39.35 years; 62.5% women) across five escitalopram trials.
- Trials evaluated oral monotherapy with psychedelics (psilocybin, lysergic acid diethylamide, 3,4-methylenedioxymethamphetamine [MDMA], and ayahuasca), fixed-dose escitalopram (up to 20 mg/d) versus placebo, and psychedelic versus escitalopram monotherapy.
- The primary outcome was a change in depressive symptoms from baseline.
TAKEAWAY:
- Placebo responses in antidepressant trials (mean difference, 3.79; 95% CI, 0.77-6.80) and extremely low-dose psilocybin (mean difference, 3.96; 95% CI, 0.61-7.17) were better than those in psychedelic trials.
- High-dose psilocybin (20 mg or more) performed better than placebo in the antidepressant trials (mean difference, > 3). However, when comparing high-dose psilocybin with the placebo used in antidepressant trials, the effect size was smaller. The standardized mean difference dropped from 0.88 to 0.31, indicating that the effect of high-dose psilocybin was similar to that of current antidepressants.
- High-dose psilocybin was associated with a greater response than escitalopram at 10 mg (4.66; 95% CI, 1.36-7.74) and 20 mg (4.69; 95% CI, 1.64-7.54).
- No interventions were associated with an increased risk for all-cause discontinuation or severe adverse events.
IN PRACTICE:
“Taken together, our study findings suggest that among psychedelic treatments, high-dose psilocybin is more likely to reach the minimal important difference for depressive symptoms in studies with adequate blinding design, while the effect size of psilocybin was similar to that of current antidepressant drugs, showing a mean standardized mean difference of 0.3,” the authors wrote.
SOURCE:
The study was led by Tien-Wei Hsu, MD, I-Shou University and Kaohsiung Medical University, Kaohsiung City, Taiwan. It was published online in The BMJ.
LIMITATIONS:
The study did not assess long-term effects of the interventions. Participants in the MDMA trials were primarily diagnosed with posttraumatic stress disorder, which may not be representative of the general population with depressive symptoms. Moreover, the sample size of the psychedelic trials was small. Using extremely low-dose psychedelics as a reference group may have eliminated some pharmacologic effects as these doses cannot be considered a placebo.
DISCLOSURES:
The study was supported by grants from the National Science and Technology Council. The authors declared no financial relationships with any organizations outside the submitted work in the past 3 years. Full disclosures are available in the original article.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.
Gabapentin: The Hope, the Harm, the Myth, the Reality
Since gabapentin was approved by the US Food and Drug Administration (FDA) for treatment of partial-onset seizures and postherpetic neuralgia, it has been used in many different ways, many off-label indications, and with several recent safety warnings.
Early Problems
After FDA approval in 1993 (for partial seizures), gabapentin was promoted by its maker (Park-Davis) for off-label indications, especially for pain. There was no FDA approval for that indication and the studies the company had done were deemed to have been manipulated in a subsequent lawsuit.1 Gabapentin became the nonopioid go-to medication for treatment of pain despite underwhelming evidence.
Studies on Neuropathy
In the largest trial of gabapentin for diabetic peripheral neuropathy, Rauck and colleagues found no significant difference in pain relief between gabapentin and placebo.2 A Cochrane review of gabapentin for neuropathic pain concluded that about 30%-40% of patients taking gabapentin for diabetic neuropathy achieved meaningful pain relief with gabapentin use, with a number needed to treat (NNT) of 6.6.3 The review also concluded that for postherpetic neuralgia (an FDA-approved indication) 78% of patients had moderate to substantial benefit with gabapentin (NNT 4.8 for moderate benefit).
Side Effects of Gabapentin
From the Cochrane review, the most common side effects were: dizziness (19%), somnolence (14%), peripheral edema (7%), and gait disturbance (14%). The number needed to harm for gabapentin was 7.5 The two side effects listed here that are often overlooked that I want to highlight are peripheral edema and gait disturbance. I have seen these both fairly frequently over the years. A side effect not found in the Cochrane review was weight gain. Weight gain with gabapentin was reported in a meta-analysis of drugs that can cause weight gain.4
New Warnings
In December 2019, the FDA released a warning on the potential for serious respiratory problems with gabapentin and pregabalin in patients with certain risk factors: opioid use or use of other drugs that depress the central nervous system, COPD, and other severe lung diseases.5 Rahman and colleagues found that compared with nonuse, gabapentinoid use was associated with increased risk for severe COPD exacerbation (hazard ratio, 1.39; 95% confidence interval, 1.29-1.50).6
Off-Label Uses
Primary care professionals frequently use gabapentin for two off-label indications that are incorporated into practice guidelines. Ryan et al. studied gabapentin in patients with refractory, unexplained chronic cough.7 In a randomized, placebo-controlled trial, gabapentin improved cough-specific quality of life compared with placebo (P = .004; NNT 3.58). Use of gabapentin for treatment of unexplained, refractory cough has been included in several chronic cough practice guidelines.8,9
Gabapentin has been studied for the treatment of restless legs syndrome and has been recommended as an option to treat moderate to severe restless legs syndrome in the American Academy of Sleep Medicine Guidelines.10
Pearl of the Month:
Gabapentin is used widely for many different pain syndromes. The best evidence is for postherpetic neuralgia and diabetic neuropathy. Be aware of the side effects and risks of use in patients with pulmonary disease and who are taking CNS-depressant medications.
Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and he serves as third-year medical student clerkship director at the University of Washington. He is a member of the editorial advisory board of Internal Medicine News. Dr. Paauw has no conflicts to disclose. Contact him at [email protected].
References
1. Landefeld CS, Steinman MA. The Neurontin legacy: marketing through misinformation and manipulation. N Engl J Med. 2009;360(2):103-6.
2. Rauck R et al. A randomized, controlled trial of gabapentin enacarbil in subjects with neuropathic pain associated with diabetic peripheral neuropathy. Pain Pract. 2013;13(6):485-96.
3. Wiffen PJ et al. Gabapentin for chronic neuropathic pain in adults. Cochrane Database Syst Rev. 2017;6(6):CD007938.
4. Domecq JP et al. Clinical review: Drugs commonly associated with weight change: a systematic review and meta-analysis. J Clin Endocrinol Metab. 2015 Feb;100(2):363-70.
5. 12-19-2019 FDA Drug Safety Communication. FDA warns about serious breathing problems with seizure and nerve pain medicines gabapentin (Neurontin, Gralise, Horizant) and pregabalin (Lyrica, Lyrica CR).
6. Rahman AA et al. Gabapentinoids and risk for severe exacerbation in chronic obstructive pulmonary disease: A population-based cohort study. Ann Intern Med. 2024 Feb;177(2):144-54.
7. Ryan NM et al. Gabapentin for refractory chronic cough: a randomised, double-blind, placebo-controlled trial. Lancet 2012;380(9853):1583-9.
8. Gibson P et al. Treatment of unexplained chronic cough: CHEST guideline and expert panel report. Chest. 2016 Jan;149(1):27-44.
9. De Vincentis A et al. Chronic cough in adults: recommendations from an Italian intersociety consensus. Aging Clin Exp Res 2022;34:1529.
10. Aurora RN et al. The treatment of restless legs syndrome and periodic limb movement disorder in adults — an update for 2012: Practice parameters with an evidence-based systematic review and meta-analyses: An American Academy of Sleep Medicine Clinical Practice Guideline. Sleep 2012;35:1039.
Since gabapentin was approved by the US Food and Drug Administration (FDA) for treatment of partial-onset seizures and postherpetic neuralgia, it has been used in many different ways, many off-label indications, and with several recent safety warnings.
Early Problems
After FDA approval in 1993 (for partial seizures), gabapentin was promoted by its maker (Park-Davis) for off-label indications, especially for pain. There was no FDA approval for that indication and the studies the company had done were deemed to have been manipulated in a subsequent lawsuit.1 Gabapentin became the nonopioid go-to medication for treatment of pain despite underwhelming evidence.
Studies on Neuropathy
In the largest trial of gabapentin for diabetic peripheral neuropathy, Rauck and colleagues found no significant difference in pain relief between gabapentin and placebo.2 A Cochrane review of gabapentin for neuropathic pain concluded that about 30%-40% of patients taking gabapentin for diabetic neuropathy achieved meaningful pain relief with gabapentin use, with a number needed to treat (NNT) of 6.6.3 The review also concluded that for postherpetic neuralgia (an FDA-approved indication) 78% of patients had moderate to substantial benefit with gabapentin (NNT 4.8 for moderate benefit).
Side Effects of Gabapentin
From the Cochrane review, the most common side effects were: dizziness (19%), somnolence (14%), peripheral edema (7%), and gait disturbance (14%). The number needed to harm for gabapentin was 7.5 The two side effects listed here that are often overlooked that I want to highlight are peripheral edema and gait disturbance. I have seen these both fairly frequently over the years. A side effect not found in the Cochrane review was weight gain. Weight gain with gabapentin was reported in a meta-analysis of drugs that can cause weight gain.4
New Warnings
In December 2019, the FDA released a warning on the potential for serious respiratory problems with gabapentin and pregabalin in patients with certain risk factors: opioid use or use of other drugs that depress the central nervous system, COPD, and other severe lung diseases.5 Rahman and colleagues found that compared with nonuse, gabapentinoid use was associated with increased risk for severe COPD exacerbation (hazard ratio, 1.39; 95% confidence interval, 1.29-1.50).6
Off-Label Uses
Primary care professionals frequently use gabapentin for two off-label indications that are incorporated into practice guidelines. Ryan et al. studied gabapentin in patients with refractory, unexplained chronic cough.7 In a randomized, placebo-controlled trial, gabapentin improved cough-specific quality of life compared with placebo (P = .004; NNT 3.58). Use of gabapentin for treatment of unexplained, refractory cough has been included in several chronic cough practice guidelines.8,9
Gabapentin has been studied for the treatment of restless legs syndrome and has been recommended as an option to treat moderate to severe restless legs syndrome in the American Academy of Sleep Medicine Guidelines.10
Pearl of the Month:
Gabapentin is used widely for many different pain syndromes. The best evidence is for postherpetic neuralgia and diabetic neuropathy. Be aware of the side effects and risks of use in patients with pulmonary disease and who are taking CNS-depressant medications.
Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and he serves as third-year medical student clerkship director at the University of Washington. He is a member of the editorial advisory board of Internal Medicine News. Dr. Paauw has no conflicts to disclose. Contact him at [email protected].
References
1. Landefeld CS, Steinman MA. The Neurontin legacy: marketing through misinformation and manipulation. N Engl J Med. 2009;360(2):103-6.
2. Rauck R et al. A randomized, controlled trial of gabapentin enacarbil in subjects with neuropathic pain associated with diabetic peripheral neuropathy. Pain Pract. 2013;13(6):485-96.
3. Wiffen PJ et al. Gabapentin for chronic neuropathic pain in adults. Cochrane Database Syst Rev. 2017;6(6):CD007938.
4. Domecq JP et al. Clinical review: Drugs commonly associated with weight change: a systematic review and meta-analysis. J Clin Endocrinol Metab. 2015 Feb;100(2):363-70.
5. 12-19-2019 FDA Drug Safety Communication. FDA warns about serious breathing problems with seizure and nerve pain medicines gabapentin (Neurontin, Gralise, Horizant) and pregabalin (Lyrica, Lyrica CR).
6. Rahman AA et al. Gabapentinoids and risk for severe exacerbation in chronic obstructive pulmonary disease: A population-based cohort study. Ann Intern Med. 2024 Feb;177(2):144-54.
7. Ryan NM et al. Gabapentin for refractory chronic cough: a randomised, double-blind, placebo-controlled trial. Lancet 2012;380(9853):1583-9.
8. Gibson P et al. Treatment of unexplained chronic cough: CHEST guideline and expert panel report. Chest. 2016 Jan;149(1):27-44.
9. De Vincentis A et al. Chronic cough in adults: recommendations from an Italian intersociety consensus. Aging Clin Exp Res 2022;34:1529.
10. Aurora RN et al. The treatment of restless legs syndrome and periodic limb movement disorder in adults — an update for 2012: Practice parameters with an evidence-based systematic review and meta-analyses: An American Academy of Sleep Medicine Clinical Practice Guideline. Sleep 2012;35:1039.
Since gabapentin was approved by the US Food and Drug Administration (FDA) for treatment of partial-onset seizures and postherpetic neuralgia, it has been used in many different ways, many off-label indications, and with several recent safety warnings.
Early Problems
After FDA approval in 1993 (for partial seizures), gabapentin was promoted by its maker (Park-Davis) for off-label indications, especially for pain. There was no FDA approval for that indication and the studies the company had done were deemed to have been manipulated in a subsequent lawsuit.1 Gabapentin became the nonopioid go-to medication for treatment of pain despite underwhelming evidence.
Studies on Neuropathy
In the largest trial of gabapentin for diabetic peripheral neuropathy, Rauck and colleagues found no significant difference in pain relief between gabapentin and placebo.2 A Cochrane review of gabapentin for neuropathic pain concluded that about 30%-40% of patients taking gabapentin for diabetic neuropathy achieved meaningful pain relief with gabapentin use, with a number needed to treat (NNT) of 6.6.3 The review also concluded that for postherpetic neuralgia (an FDA-approved indication) 78% of patients had moderate to substantial benefit with gabapentin (NNT 4.8 for moderate benefit).
Side Effects of Gabapentin
From the Cochrane review, the most common side effects were: dizziness (19%), somnolence (14%), peripheral edema (7%), and gait disturbance (14%). The number needed to harm for gabapentin was 7.5 The two side effects listed here that are often overlooked that I want to highlight are peripheral edema and gait disturbance. I have seen these both fairly frequently over the years. A side effect not found in the Cochrane review was weight gain. Weight gain with gabapentin was reported in a meta-analysis of drugs that can cause weight gain.4
New Warnings
In December 2019, the FDA released a warning on the potential for serious respiratory problems with gabapentin and pregabalin in patients with certain risk factors: opioid use or use of other drugs that depress the central nervous system, COPD, and other severe lung diseases.5 Rahman and colleagues found that compared with nonuse, gabapentinoid use was associated with increased risk for severe COPD exacerbation (hazard ratio, 1.39; 95% confidence interval, 1.29-1.50).6
Off-Label Uses
Primary care professionals frequently use gabapentin for two off-label indications that are incorporated into practice guidelines. Ryan et al. studied gabapentin in patients with refractory, unexplained chronic cough.7 In a randomized, placebo-controlled trial, gabapentin improved cough-specific quality of life compared with placebo (P = .004; NNT 3.58). Use of gabapentin for treatment of unexplained, refractory cough has been included in several chronic cough practice guidelines.8,9
Gabapentin has been studied for the treatment of restless legs syndrome and has been recommended as an option to treat moderate to severe restless legs syndrome in the American Academy of Sleep Medicine Guidelines.10
Pearl of the Month:
Gabapentin is used widely for many different pain syndromes. The best evidence is for postherpetic neuralgia and diabetic neuropathy. Be aware of the side effects and risks of use in patients with pulmonary disease and who are taking CNS-depressant medications.
Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and he serves as third-year medical student clerkship director at the University of Washington. He is a member of the editorial advisory board of Internal Medicine News. Dr. Paauw has no conflicts to disclose. Contact him at [email protected].
References
1. Landefeld CS, Steinman MA. The Neurontin legacy: marketing through misinformation and manipulation. N Engl J Med. 2009;360(2):103-6.
2. Rauck R et al. A randomized, controlled trial of gabapentin enacarbil in subjects with neuropathic pain associated with diabetic peripheral neuropathy. Pain Pract. 2013;13(6):485-96.
3. Wiffen PJ et al. Gabapentin for chronic neuropathic pain in adults. Cochrane Database Syst Rev. 2017;6(6):CD007938.
4. Domecq JP et al. Clinical review: Drugs commonly associated with weight change: a systematic review and meta-analysis. J Clin Endocrinol Metab. 2015 Feb;100(2):363-70.
5. 12-19-2019 FDA Drug Safety Communication. FDA warns about serious breathing problems with seizure and nerve pain medicines gabapentin (Neurontin, Gralise, Horizant) and pregabalin (Lyrica, Lyrica CR).
6. Rahman AA et al. Gabapentinoids and risk for severe exacerbation in chronic obstructive pulmonary disease: A population-based cohort study. Ann Intern Med. 2024 Feb;177(2):144-54.
7. Ryan NM et al. Gabapentin for refractory chronic cough: a randomised, double-blind, placebo-controlled trial. Lancet 2012;380(9853):1583-9.
8. Gibson P et al. Treatment of unexplained chronic cough: CHEST guideline and expert panel report. Chest. 2016 Jan;149(1):27-44.
9. De Vincentis A et al. Chronic cough in adults: recommendations from an Italian intersociety consensus. Aging Clin Exp Res 2022;34:1529.
10. Aurora RN et al. The treatment of restless legs syndrome and periodic limb movement disorder in adults — an update for 2012: Practice parameters with an evidence-based systematic review and meta-analyses: An American Academy of Sleep Medicine Clinical Practice Guideline. Sleep 2012;35:1039.
Signal of Suicide Ideation With GLP-1 RA Semaglutide, but Experts Urge Caution
A new analysis has detected a signal of suicidal ideation associated with the glucagon-like peptide 1 receptor agonist (GLP-1 RA) semaglutide, especially among individuals concurrently using antidepressants or benzodiazepines.
However, the investigators and outside experts urge caution in drawing any firm conclusions based on the study’s observations.
,” study investigator Georgios Schoretsanitis, MD, PhD, Department of Psychiatry, The Zucker Hillside Hospital, Northwell Health, Glen Oaks, New York, told this news organization.
Nonetheless, “physicians prescribing semaglutide should inform their patients about the medications’ risks and assess the psychiatric history and evaluate the mental state of patients before starting treatment with semaglutide,” Dr. Schoretsanitis said.
“For patients with history of mental disorders or suicidal ideation/behaviors/attempts, physicians should be cautious and regularly monitor their mental state while taking semaglutide. If needed, the treating physician should involve different specialists, including a psychiatrist and/or clinical psychologists,” he added.
The study was published online on August 20 in JAMA Network Open.
Emerging Concerns
GLP-1 RAs are increasingly prescribed not only for type 2 diabetes but also for weight loss. However, concerns have emerged about a potential association with suicidality, which has prompted a closer look by regulators in the United States and Europe.
Dr. Schoretsanitis and colleagues evaluated potential signals of suicidality related to semaglutide and liraglutide using data from global World Health Organization database of suspected adverse drug reactions (ADRs).
They conducted sensitivity analyses including patients with co-reported use of antidepressants and benzodiazepines and using dapagliflozin, metformin, and orlistat as comparators.
Between November 2000 and August 2023, there were 107 cases of suicidal and/or self-injurious ADRs reported with semaglutide (median age, 48 years; 55% women) and 162 reported with liraglutide (median age 47 years; 61% women).
The researchers noted that a “significant disproportionality” signal emerged for semaglutide-associated suicidal ideation (reporting odds ratio [ROR], 1.45), when compared with comparator drugs.
This signal remained significant in sensitivity analyses that included patients on concurrent antidepressants (ROR, 4.45) and benzodiazepines (ROR, 4.07), “suggesting that people with anxiety and depressive disorders may be at higher probability of reporting suicidal ideation when medicated with semaglutide,” the authors wrote.
No significant disproportionality signal was detected for liraglutide regarding suicidal ideation (ROR, 1.04).
However, the authors noted that pooled data from previous phase 2 and 3 trials on liraglutide vs placebo for weight management identified a potential risk for suicidal ideation, with nine of 3384 participants in the liraglutide group vs two of 1941 in the placebo group reporting suicidal ideation or behavior during the trial (0.27% vs 0.10%).
More Research Needed
GLP-1 RAs “should be used cautiously until further data are available on this topic,” Dr. Schoretsanitis said.
“Further real-world studies should investigate the risk of suicidal ideation or behavior in people treated with these drugs in every-day clinical practice. We categorically discourage off-label use of GLP1-RA and without any medical supervision,” he added.
The coauthors of an invited commentary published with the study note that between 2020 and 2023, GLP-1 RA use rose 594% in younger people, particularly in women.
This “timely and well-conducted study” by Dr. Schoretsanitis and colleagues adds “an important piece to the very relevant safety issue” related to GLP-1 RAs, wrote Francesco Salvo, MD, PhD, with Université de Bordeaux, and Jean-Luc Faillie, MD, PhD, with Université de Montpellier, both in France.
Pending further studies, the position of the US Food and Drug Administration (FDA) recommending caution “continues to be reasonable. Whatever the cause, depression or suicidality are rare but extremely severe events and need to be prevented and managed as much as possible.
“Waiting for more precise data, GPL-1 receptor agonists, and appetite suppressants in general, should be prescribed with great caution in patients with a history of depression or suicidal attempts, while in patients with new onset of depression without other apparent precipitants, immediate discontinuation of GLP-1 receptor agonists should be considered,” wrote Dr. Salvo and Dr. Faillie.
Outside experts also weighed in on the study in a statement from the UK nonprofit Science Media Centre.
The paper presents, “at best, weak evidence of an association between semaglutide and suicidality,” Ian Douglas, PhD, professor of pharmacoepidemiology, London School of Hygiene & Tropical Medicine, United Kingdom, said in the statement. “Signal detection studies in pharmacovigilance databases are good for generating hypotheses but are not suitable for assessing whether there is a causal association between a drug and an outcome.”
Stephen Evans, MSc, emeritus professor of pharmacoepidemiology, London School of Hygiene & Tropical Medicine, cautioned that the study has “major limitations.”
“This paper is based just on spontaneous reports which are sent to regulatory authorities in the country of the person reporting a suspected adverse reaction. These are sent by health professionals and patients to authorities, but are very subject to bias, including effects of media reporting. The evidence is extremely weak for a genuine effect in this instance,” Mr. Evans said.
The study had no specific funding. Dr. Schoretsanitis reported receiving personal fees from HLS, Dexcel, Saladax, and Thermo Fisher outside the submitted work. Dr. Salvo and Dr. Faillie have no conflicts of interest. Dr. Douglas has received research grants from GSK and AstraZeneca. Mr. Evans has no conflicts of interest.
A version of this article appeared on Medscape.com.
A new analysis has detected a signal of suicidal ideation associated with the glucagon-like peptide 1 receptor agonist (GLP-1 RA) semaglutide, especially among individuals concurrently using antidepressants or benzodiazepines.
However, the investigators and outside experts urge caution in drawing any firm conclusions based on the study’s observations.
,” study investigator Georgios Schoretsanitis, MD, PhD, Department of Psychiatry, The Zucker Hillside Hospital, Northwell Health, Glen Oaks, New York, told this news organization.
Nonetheless, “physicians prescribing semaglutide should inform their patients about the medications’ risks and assess the psychiatric history and evaluate the mental state of patients before starting treatment with semaglutide,” Dr. Schoretsanitis said.
“For patients with history of mental disorders or suicidal ideation/behaviors/attempts, physicians should be cautious and regularly monitor their mental state while taking semaglutide. If needed, the treating physician should involve different specialists, including a psychiatrist and/or clinical psychologists,” he added.
The study was published online on August 20 in JAMA Network Open.
Emerging Concerns
GLP-1 RAs are increasingly prescribed not only for type 2 diabetes but also for weight loss. However, concerns have emerged about a potential association with suicidality, which has prompted a closer look by regulators in the United States and Europe.
Dr. Schoretsanitis and colleagues evaluated potential signals of suicidality related to semaglutide and liraglutide using data from global World Health Organization database of suspected adverse drug reactions (ADRs).
They conducted sensitivity analyses including patients with co-reported use of antidepressants and benzodiazepines and using dapagliflozin, metformin, and orlistat as comparators.
Between November 2000 and August 2023, there were 107 cases of suicidal and/or self-injurious ADRs reported with semaglutide (median age, 48 years; 55% women) and 162 reported with liraglutide (median age 47 years; 61% women).
The researchers noted that a “significant disproportionality” signal emerged for semaglutide-associated suicidal ideation (reporting odds ratio [ROR], 1.45), when compared with comparator drugs.
This signal remained significant in sensitivity analyses that included patients on concurrent antidepressants (ROR, 4.45) and benzodiazepines (ROR, 4.07), “suggesting that people with anxiety and depressive disorders may be at higher probability of reporting suicidal ideation when medicated with semaglutide,” the authors wrote.
No significant disproportionality signal was detected for liraglutide regarding suicidal ideation (ROR, 1.04).
However, the authors noted that pooled data from previous phase 2 and 3 trials on liraglutide vs placebo for weight management identified a potential risk for suicidal ideation, with nine of 3384 participants in the liraglutide group vs two of 1941 in the placebo group reporting suicidal ideation or behavior during the trial (0.27% vs 0.10%).
More Research Needed
GLP-1 RAs “should be used cautiously until further data are available on this topic,” Dr. Schoretsanitis said.
“Further real-world studies should investigate the risk of suicidal ideation or behavior in people treated with these drugs in every-day clinical practice. We categorically discourage off-label use of GLP1-RA and without any medical supervision,” he added.
The coauthors of an invited commentary published with the study note that between 2020 and 2023, GLP-1 RA use rose 594% in younger people, particularly in women.
This “timely and well-conducted study” by Dr. Schoretsanitis and colleagues adds “an important piece to the very relevant safety issue” related to GLP-1 RAs, wrote Francesco Salvo, MD, PhD, with Université de Bordeaux, and Jean-Luc Faillie, MD, PhD, with Université de Montpellier, both in France.
Pending further studies, the position of the US Food and Drug Administration (FDA) recommending caution “continues to be reasonable. Whatever the cause, depression or suicidality are rare but extremely severe events and need to be prevented and managed as much as possible.
“Waiting for more precise data, GPL-1 receptor agonists, and appetite suppressants in general, should be prescribed with great caution in patients with a history of depression or suicidal attempts, while in patients with new onset of depression without other apparent precipitants, immediate discontinuation of GLP-1 receptor agonists should be considered,” wrote Dr. Salvo and Dr. Faillie.
Outside experts also weighed in on the study in a statement from the UK nonprofit Science Media Centre.
The paper presents, “at best, weak evidence of an association between semaglutide and suicidality,” Ian Douglas, PhD, professor of pharmacoepidemiology, London School of Hygiene & Tropical Medicine, United Kingdom, said in the statement. “Signal detection studies in pharmacovigilance databases are good for generating hypotheses but are not suitable for assessing whether there is a causal association between a drug and an outcome.”
Stephen Evans, MSc, emeritus professor of pharmacoepidemiology, London School of Hygiene & Tropical Medicine, cautioned that the study has “major limitations.”
“This paper is based just on spontaneous reports which are sent to regulatory authorities in the country of the person reporting a suspected adverse reaction. These are sent by health professionals and patients to authorities, but are very subject to bias, including effects of media reporting. The evidence is extremely weak for a genuine effect in this instance,” Mr. Evans said.
The study had no specific funding. Dr. Schoretsanitis reported receiving personal fees from HLS, Dexcel, Saladax, and Thermo Fisher outside the submitted work. Dr. Salvo and Dr. Faillie have no conflicts of interest. Dr. Douglas has received research grants from GSK and AstraZeneca. Mr. Evans has no conflicts of interest.
A version of this article appeared on Medscape.com.
A new analysis has detected a signal of suicidal ideation associated with the glucagon-like peptide 1 receptor agonist (GLP-1 RA) semaglutide, especially among individuals concurrently using antidepressants or benzodiazepines.
However, the investigators and outside experts urge caution in drawing any firm conclusions based on the study’s observations.
,” study investigator Georgios Schoretsanitis, MD, PhD, Department of Psychiatry, The Zucker Hillside Hospital, Northwell Health, Glen Oaks, New York, told this news organization.
Nonetheless, “physicians prescribing semaglutide should inform their patients about the medications’ risks and assess the psychiatric history and evaluate the mental state of patients before starting treatment with semaglutide,” Dr. Schoretsanitis said.
“For patients with history of mental disorders or suicidal ideation/behaviors/attempts, physicians should be cautious and regularly monitor their mental state while taking semaglutide. If needed, the treating physician should involve different specialists, including a psychiatrist and/or clinical psychologists,” he added.
The study was published online on August 20 in JAMA Network Open.
Emerging Concerns
GLP-1 RAs are increasingly prescribed not only for type 2 diabetes but also for weight loss. However, concerns have emerged about a potential association with suicidality, which has prompted a closer look by regulators in the United States and Europe.
Dr. Schoretsanitis and colleagues evaluated potential signals of suicidality related to semaglutide and liraglutide using data from global World Health Organization database of suspected adverse drug reactions (ADRs).
They conducted sensitivity analyses including patients with co-reported use of antidepressants and benzodiazepines and using dapagliflozin, metformin, and orlistat as comparators.
Between November 2000 and August 2023, there were 107 cases of suicidal and/or self-injurious ADRs reported with semaglutide (median age, 48 years; 55% women) and 162 reported with liraglutide (median age 47 years; 61% women).
The researchers noted that a “significant disproportionality” signal emerged for semaglutide-associated suicidal ideation (reporting odds ratio [ROR], 1.45), when compared with comparator drugs.
This signal remained significant in sensitivity analyses that included patients on concurrent antidepressants (ROR, 4.45) and benzodiazepines (ROR, 4.07), “suggesting that people with anxiety and depressive disorders may be at higher probability of reporting suicidal ideation when medicated with semaglutide,” the authors wrote.
No significant disproportionality signal was detected for liraglutide regarding suicidal ideation (ROR, 1.04).
However, the authors noted that pooled data from previous phase 2 and 3 trials on liraglutide vs placebo for weight management identified a potential risk for suicidal ideation, with nine of 3384 participants in the liraglutide group vs two of 1941 in the placebo group reporting suicidal ideation or behavior during the trial (0.27% vs 0.10%).
More Research Needed
GLP-1 RAs “should be used cautiously until further data are available on this topic,” Dr. Schoretsanitis said.
“Further real-world studies should investigate the risk of suicidal ideation or behavior in people treated with these drugs in every-day clinical practice. We categorically discourage off-label use of GLP1-RA and without any medical supervision,” he added.
The coauthors of an invited commentary published with the study note that between 2020 and 2023, GLP-1 RA use rose 594% in younger people, particularly in women.
This “timely and well-conducted study” by Dr. Schoretsanitis and colleagues adds “an important piece to the very relevant safety issue” related to GLP-1 RAs, wrote Francesco Salvo, MD, PhD, with Université de Bordeaux, and Jean-Luc Faillie, MD, PhD, with Université de Montpellier, both in France.
Pending further studies, the position of the US Food and Drug Administration (FDA) recommending caution “continues to be reasonable. Whatever the cause, depression or suicidality are rare but extremely severe events and need to be prevented and managed as much as possible.
“Waiting for more precise data, GPL-1 receptor agonists, and appetite suppressants in general, should be prescribed with great caution in patients with a history of depression or suicidal attempts, while in patients with new onset of depression without other apparent precipitants, immediate discontinuation of GLP-1 receptor agonists should be considered,” wrote Dr. Salvo and Dr. Faillie.
Outside experts also weighed in on the study in a statement from the UK nonprofit Science Media Centre.
The paper presents, “at best, weak evidence of an association between semaglutide and suicidality,” Ian Douglas, PhD, professor of pharmacoepidemiology, London School of Hygiene & Tropical Medicine, United Kingdom, said in the statement. “Signal detection studies in pharmacovigilance databases are good for generating hypotheses but are not suitable for assessing whether there is a causal association between a drug and an outcome.”
Stephen Evans, MSc, emeritus professor of pharmacoepidemiology, London School of Hygiene & Tropical Medicine, cautioned that the study has “major limitations.”
“This paper is based just on spontaneous reports which are sent to regulatory authorities in the country of the person reporting a suspected adverse reaction. These are sent by health professionals and patients to authorities, but are very subject to bias, including effects of media reporting. The evidence is extremely weak for a genuine effect in this instance,” Mr. Evans said.
The study had no specific funding. Dr. Schoretsanitis reported receiving personal fees from HLS, Dexcel, Saladax, and Thermo Fisher outside the submitted work. Dr. Salvo and Dr. Faillie have no conflicts of interest. Dr. Douglas has received research grants from GSK and AstraZeneca. Mr. Evans has no conflicts of interest.
A version of this article appeared on Medscape.com.
Veterans Found Relief From Chronic Pain Through Telehealth Mindfulness
TOPLINE:
METHODOLOGY:
- Researchers conducted a randomized clinical trial of 811 veterans who had moderate to severe chronic pain and were recruited from three Veterans Affairs facilities in the United States.
- Participants were divided into three groups: Group MBI (270), self-paced MBI (271), and usual care (270), with interventions lasting 8 weeks.
- The primary outcome was pain-related function measured using a scale on interference from pain in areas like mood, walking, work, relationships, and sleep at 10 weeks, 6 months, and 1 year.
- Secondary outcomes included pain intensity, anxiety, fatigue, sleep disturbance, participation in social roles and activities, depression, and posttraumatic stress disorder (PTSD).
TAKEAWAY:
- Pain-related function significantly improved in participants in both the MBI groups versus usual care group, with a mean difference of −0.4 (95% CI, −0.7 to −0.2) for group MBI and −0.7 (95% CI, −1.0 to −0.4) for self-paced MBI (P < .001).
- Compared with the usual care group, both the MBI groups had significantly improved secondary outcomes, including pain intensity, depression, and PTSD.
- The probability of achieving 30% improvement in pain-related function was higher for group MBI at 10 weeks and 6 months and for self-paced MBI at all three timepoints.
- No significant differences were found between the MBI groups for primary and secondary outcomes.
IN PRACTICE:
“The viability and similarity of both these approaches for delivering MBIs increase patient options for meeting their individual needs and could help accelerate and improve the implementation of nonpharmacological pain treatment in health care systems,” the study authors wrote.
SOURCE:
The study was led by Diana J. Burgess, PhD, of the Center for Care Delivery and Outcomes Research, VA Health Systems Research in Minneapolis, Minnesota, and published online in JAMA Internal Medicine.
LIMITATIONS:
The trial was not designed to compare less resource-intensive MBIs with more intensive mindfulness-based stress reduction programs or in-person MBIs. The study did not address cost-effectiveness or control for time, attention, and other contextual factors. The high nonresponse rate (81%) to initial recruitment may have affected the generalizability of the findings.
DISCLOSURES:
The study was supported by the Pain Management Collaboratory–Pragmatic Clinical Trials Demonstration. Various authors reported grants from the National Center for Complementary and Integrative Health and the National Institute of Nursing Research.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.
TOPLINE:
METHODOLOGY:
- Researchers conducted a randomized clinical trial of 811 veterans who had moderate to severe chronic pain and were recruited from three Veterans Affairs facilities in the United States.
- Participants were divided into three groups: Group MBI (270), self-paced MBI (271), and usual care (270), with interventions lasting 8 weeks.
- The primary outcome was pain-related function measured using a scale on interference from pain in areas like mood, walking, work, relationships, and sleep at 10 weeks, 6 months, and 1 year.
- Secondary outcomes included pain intensity, anxiety, fatigue, sleep disturbance, participation in social roles and activities, depression, and posttraumatic stress disorder (PTSD).
TAKEAWAY:
- Pain-related function significantly improved in participants in both the MBI groups versus usual care group, with a mean difference of −0.4 (95% CI, −0.7 to −0.2) for group MBI and −0.7 (95% CI, −1.0 to −0.4) for self-paced MBI (P < .001).
- Compared with the usual care group, both the MBI groups had significantly improved secondary outcomes, including pain intensity, depression, and PTSD.
- The probability of achieving 30% improvement in pain-related function was higher for group MBI at 10 weeks and 6 months and for self-paced MBI at all three timepoints.
- No significant differences were found between the MBI groups for primary and secondary outcomes.
IN PRACTICE:
“The viability and similarity of both these approaches for delivering MBIs increase patient options for meeting their individual needs and could help accelerate and improve the implementation of nonpharmacological pain treatment in health care systems,” the study authors wrote.
SOURCE:
The study was led by Diana J. Burgess, PhD, of the Center for Care Delivery and Outcomes Research, VA Health Systems Research in Minneapolis, Minnesota, and published online in JAMA Internal Medicine.
LIMITATIONS:
The trial was not designed to compare less resource-intensive MBIs with more intensive mindfulness-based stress reduction programs or in-person MBIs. The study did not address cost-effectiveness or control for time, attention, and other contextual factors. The high nonresponse rate (81%) to initial recruitment may have affected the generalizability of the findings.
DISCLOSURES:
The study was supported by the Pain Management Collaboratory–Pragmatic Clinical Trials Demonstration. Various authors reported grants from the National Center for Complementary and Integrative Health and the National Institute of Nursing Research.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.
TOPLINE:
METHODOLOGY:
- Researchers conducted a randomized clinical trial of 811 veterans who had moderate to severe chronic pain and were recruited from three Veterans Affairs facilities in the United States.
- Participants were divided into three groups: Group MBI (270), self-paced MBI (271), and usual care (270), with interventions lasting 8 weeks.
- The primary outcome was pain-related function measured using a scale on interference from pain in areas like mood, walking, work, relationships, and sleep at 10 weeks, 6 months, and 1 year.
- Secondary outcomes included pain intensity, anxiety, fatigue, sleep disturbance, participation in social roles and activities, depression, and posttraumatic stress disorder (PTSD).
TAKEAWAY:
- Pain-related function significantly improved in participants in both the MBI groups versus usual care group, with a mean difference of −0.4 (95% CI, −0.7 to −0.2) for group MBI and −0.7 (95% CI, −1.0 to −0.4) for self-paced MBI (P < .001).
- Compared with the usual care group, both the MBI groups had significantly improved secondary outcomes, including pain intensity, depression, and PTSD.
- The probability of achieving 30% improvement in pain-related function was higher for group MBI at 10 weeks and 6 months and for self-paced MBI at all three timepoints.
- No significant differences were found between the MBI groups for primary and secondary outcomes.
IN PRACTICE:
“The viability and similarity of both these approaches for delivering MBIs increase patient options for meeting their individual needs and could help accelerate and improve the implementation of nonpharmacological pain treatment in health care systems,” the study authors wrote.
SOURCE:
The study was led by Diana J. Burgess, PhD, of the Center for Care Delivery and Outcomes Research, VA Health Systems Research in Minneapolis, Minnesota, and published online in JAMA Internal Medicine.
LIMITATIONS:
The trial was not designed to compare less resource-intensive MBIs with more intensive mindfulness-based stress reduction programs or in-person MBIs. The study did not address cost-effectiveness or control for time, attention, and other contextual factors. The high nonresponse rate (81%) to initial recruitment may have affected the generalizability of the findings.
DISCLOSURES:
The study was supported by the Pain Management Collaboratory–Pragmatic Clinical Trials Demonstration. Various authors reported grants from the National Center for Complementary and Integrative Health and the National Institute of Nursing Research.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.
Hearing Loss, Neuropathy Cut Survival in Older Adults
TOPLINE:
METHODOLOGY:
- Researchers analyzed 793 older adults recruited from primary care practices participating in the OKLAHOMA Studies in 1999.
- Participants completed a questionnaire and underwent a physical examination; timed gait assessments (50 ft); and tests for peripheral nerve function, balance, and hearing.
- Hearing thresholds were tested at 20, 25, and 40 dB, respectively, and at sound frequencies of 500, 1000, 2000, and 4000 Hz.
- Researchers tracked mortality data over 22 years.
TAKEAWAY:
- Overall, 83% participants experienced hearing loss. Regular use of hearing aids was low, reported in 19% and 55% of those with moderate and severe hearing loss, respectively.
- Hearing loss was linked to impaired balance (P = .0014), slower walking (P = .0024), and reduced survival time (P = .0001). Moderate to severe hearing loss was strongly associated with reduced survival time (odds ratio, 1.36; P = .001), independent of the use of hearing aids.
- Peripheral neuropathy was present in 32% participants. The condition also increased the risk for death over the study period (hazard ratio [HR], 1.32; P = .003). Participants with both hearing loss and peripheral neuropathy showed reduced balance and survival time compared with people with either condition alone (HR, 1.55; P < .0001).
IN PRACTICE:
“Like peripheral neuropathy, advanced-age hearing loss is associated with reduced life expectancy, probably mediated in part through an adverse impact on balance,” the authors wrote. “Greater appreciation for the serious impacts of hearing loss and peripheral neuropathy could lead to further efforts to understand their causes and improve prevention and treatment strategies.”
SOURCE:
The study was led by James W. Mold, MD, MPH, of the University of Oklahoma Health Sciences Center, Oklahoma City. It was published online in the Journal of the American Geriatrics Society.
LIMITATIONS:
The dataset was collected in 1999 and may not entirely represent the current cohorts of older primary care patients. The absence of soundproof rooms and the exclusion of some components of the standard audiometric evaluation may have affected low-frequency sound measurements. Furthermore, physical examination was a less accurate measure of peripheral neuropathy. Information on the duration or severity of predictors and causes of death was not available.
DISCLOSURES:
The study was funded by the Presbyterian Health Foundation. The authors did not disclose any competing interests.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.
TOPLINE:
METHODOLOGY:
- Researchers analyzed 793 older adults recruited from primary care practices participating in the OKLAHOMA Studies in 1999.
- Participants completed a questionnaire and underwent a physical examination; timed gait assessments (50 ft); and tests for peripheral nerve function, balance, and hearing.
- Hearing thresholds were tested at 20, 25, and 40 dB, respectively, and at sound frequencies of 500, 1000, 2000, and 4000 Hz.
- Researchers tracked mortality data over 22 years.
TAKEAWAY:
- Overall, 83% participants experienced hearing loss. Regular use of hearing aids was low, reported in 19% and 55% of those with moderate and severe hearing loss, respectively.
- Hearing loss was linked to impaired balance (P = .0014), slower walking (P = .0024), and reduced survival time (P = .0001). Moderate to severe hearing loss was strongly associated with reduced survival time (odds ratio, 1.36; P = .001), independent of the use of hearing aids.
- Peripheral neuropathy was present in 32% participants. The condition also increased the risk for death over the study period (hazard ratio [HR], 1.32; P = .003). Participants with both hearing loss and peripheral neuropathy showed reduced balance and survival time compared with people with either condition alone (HR, 1.55; P < .0001).
IN PRACTICE:
“Like peripheral neuropathy, advanced-age hearing loss is associated with reduced life expectancy, probably mediated in part through an adverse impact on balance,” the authors wrote. “Greater appreciation for the serious impacts of hearing loss and peripheral neuropathy could lead to further efforts to understand their causes and improve prevention and treatment strategies.”
SOURCE:
The study was led by James W. Mold, MD, MPH, of the University of Oklahoma Health Sciences Center, Oklahoma City. It was published online in the Journal of the American Geriatrics Society.
LIMITATIONS:
The dataset was collected in 1999 and may not entirely represent the current cohorts of older primary care patients. The absence of soundproof rooms and the exclusion of some components of the standard audiometric evaluation may have affected low-frequency sound measurements. Furthermore, physical examination was a less accurate measure of peripheral neuropathy. Information on the duration or severity of predictors and causes of death was not available.
DISCLOSURES:
The study was funded by the Presbyterian Health Foundation. The authors did not disclose any competing interests.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.
TOPLINE:
METHODOLOGY:
- Researchers analyzed 793 older adults recruited from primary care practices participating in the OKLAHOMA Studies in 1999.
- Participants completed a questionnaire and underwent a physical examination; timed gait assessments (50 ft); and tests for peripheral nerve function, balance, and hearing.
- Hearing thresholds were tested at 20, 25, and 40 dB, respectively, and at sound frequencies of 500, 1000, 2000, and 4000 Hz.
- Researchers tracked mortality data over 22 years.
TAKEAWAY:
- Overall, 83% participants experienced hearing loss. Regular use of hearing aids was low, reported in 19% and 55% of those with moderate and severe hearing loss, respectively.
- Hearing loss was linked to impaired balance (P = .0014), slower walking (P = .0024), and reduced survival time (P = .0001). Moderate to severe hearing loss was strongly associated with reduced survival time (odds ratio, 1.36; P = .001), independent of the use of hearing aids.
- Peripheral neuropathy was present in 32% participants. The condition also increased the risk for death over the study period (hazard ratio [HR], 1.32; P = .003). Participants with both hearing loss and peripheral neuropathy showed reduced balance and survival time compared with people with either condition alone (HR, 1.55; P < .0001).
IN PRACTICE:
“Like peripheral neuropathy, advanced-age hearing loss is associated with reduced life expectancy, probably mediated in part through an adverse impact on balance,” the authors wrote. “Greater appreciation for the serious impacts of hearing loss and peripheral neuropathy could lead to further efforts to understand their causes and improve prevention and treatment strategies.”
SOURCE:
The study was led by James W. Mold, MD, MPH, of the University of Oklahoma Health Sciences Center, Oklahoma City. It was published online in the Journal of the American Geriatrics Society.
LIMITATIONS:
The dataset was collected in 1999 and may not entirely represent the current cohorts of older primary care patients. The absence of soundproof rooms and the exclusion of some components of the standard audiometric evaluation may have affected low-frequency sound measurements. Furthermore, physical examination was a less accurate measure of peripheral neuropathy. Information on the duration or severity of predictors and causes of death was not available.
DISCLOSURES:
The study was funded by the Presbyterian Health Foundation. The authors did not disclose any competing interests.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.
Mobile App Shows Promise in Managing Fibromyalgia Symptoms
TOPLINE:
A smartphone app that delivers acceptance and commitment therapy (ACT), a type of cognitive behavioral therapy, improves overall well-being and reduces the severity of pain, fatigue, sleep issues, and depression to a greater extent than daily symptom tracking in patients with fibromyalgia.
METHODOLOGY:
- Researchers conducted the phase 3 PROSPER-FM trial at 25 community sites in the United States to assess the efficacy and safety of digital ACT for patients with fibromyalgia.
- A total of 275 adult patients aged 22-75 years with fibromyalgia were randomly assigned to either the digital ACT group (n = 140) or the active control group (n = 135) for 12 weeks.
- Patients in the digital ACT group received a self-guided, smartphone-delivered program in which they learned and practiced the core ACT skills of acceptance, values, mindfulness, defusion, self as context, and willingness and committed action to build psychological flexibility, while the control group underwent daily symptom tracking and received educational materials.
- The primary endpoint was the response rate on the Patient Global Impression of Change (PGIC) at week 12, which is an indicator of patient well-being.
- The secondary endpoints included changes in the Revised Fibromyalgia Impact Questionnaire (FIQ-R) total score and pain intensity, pain interference, and sleep interference scores.
TAKEAWAY:
- At week 12, 71% of the patients in the digital ACT group responded with a minimally improved or better change in the PGIC response, compared with only 22% of the patients in the control group (P < .0001).
- The digital ACT group showed a significant reduction in the impact of fibromyalgia, with a between-group effect size of d = 0.65 (P < .0001) at week 12. The FIQ-R total score significantly improved within 3 weeks of using the self-guided digital ACT app.
- The use of digital ACT also demonstrated positive effects on the levels of weekly pain intensity (P = .001) and depression (P < .0001), compared with the control group.
- No serious adverse effects related to the app were reported, and both groups demonstrated high rates of adherence, with most (72%) participants in the digital ACT group completing at least 42 sessions.
IN PRACTICE:
“The results found in the study are essential for professionals who care for patients with fibromyalgia as they present a new viable treatment alternative,” Guilherme Torres Vilarino, PhD, Santa Catarina State University, Florianópolis, Brazil, wrote in an accompanying editorial.
SOURCE:
This study was led by R. Michael Gendreau, MD, PhD, Gendreau Consulting, Poway, California. It was published online in The Lancet.
LIMITATIONS:
The study population predominantly consisted of women and White individuals, which may limit the generalizability of the findings to more diverse populations. Additionally, the study was conducted in the United States, and the results may thus not be applicable to other countries with different racial, ethnic, educational, and economic characteristics. The study duration was 12 weeks, and the long-term benefits of digital ACT have not yet been shown.
DISCLOSURES:
This study was funded by Swing Therapeutics. Seven authors declared having stock options and/or receiving salary from Swing Therapeutics. Other authors reported having many ties with several sources, including Swing Therapeutics.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.
TOPLINE:
A smartphone app that delivers acceptance and commitment therapy (ACT), a type of cognitive behavioral therapy, improves overall well-being and reduces the severity of pain, fatigue, sleep issues, and depression to a greater extent than daily symptom tracking in patients with fibromyalgia.
METHODOLOGY:
- Researchers conducted the phase 3 PROSPER-FM trial at 25 community sites in the United States to assess the efficacy and safety of digital ACT for patients with fibromyalgia.
- A total of 275 adult patients aged 22-75 years with fibromyalgia were randomly assigned to either the digital ACT group (n = 140) or the active control group (n = 135) for 12 weeks.
- Patients in the digital ACT group received a self-guided, smartphone-delivered program in which they learned and practiced the core ACT skills of acceptance, values, mindfulness, defusion, self as context, and willingness and committed action to build psychological flexibility, while the control group underwent daily symptom tracking and received educational materials.
- The primary endpoint was the response rate on the Patient Global Impression of Change (PGIC) at week 12, which is an indicator of patient well-being.
- The secondary endpoints included changes in the Revised Fibromyalgia Impact Questionnaire (FIQ-R) total score and pain intensity, pain interference, and sleep interference scores.
TAKEAWAY:
- At week 12, 71% of the patients in the digital ACT group responded with a minimally improved or better change in the PGIC response, compared with only 22% of the patients in the control group (P < .0001).
- The digital ACT group showed a significant reduction in the impact of fibromyalgia, with a between-group effect size of d = 0.65 (P < .0001) at week 12. The FIQ-R total score significantly improved within 3 weeks of using the self-guided digital ACT app.
- The use of digital ACT also demonstrated positive effects on the levels of weekly pain intensity (P = .001) and depression (P < .0001), compared with the control group.
- No serious adverse effects related to the app were reported, and both groups demonstrated high rates of adherence, with most (72%) participants in the digital ACT group completing at least 42 sessions.
IN PRACTICE:
“The results found in the study are essential for professionals who care for patients with fibromyalgia as they present a new viable treatment alternative,” Guilherme Torres Vilarino, PhD, Santa Catarina State University, Florianópolis, Brazil, wrote in an accompanying editorial.
SOURCE:
This study was led by R. Michael Gendreau, MD, PhD, Gendreau Consulting, Poway, California. It was published online in The Lancet.
LIMITATIONS:
The study population predominantly consisted of women and White individuals, which may limit the generalizability of the findings to more diverse populations. Additionally, the study was conducted in the United States, and the results may thus not be applicable to other countries with different racial, ethnic, educational, and economic characteristics. The study duration was 12 weeks, and the long-term benefits of digital ACT have not yet been shown.
DISCLOSURES:
This study was funded by Swing Therapeutics. Seven authors declared having stock options and/or receiving salary from Swing Therapeutics. Other authors reported having many ties with several sources, including Swing Therapeutics.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.
TOPLINE:
A smartphone app that delivers acceptance and commitment therapy (ACT), a type of cognitive behavioral therapy, improves overall well-being and reduces the severity of pain, fatigue, sleep issues, and depression to a greater extent than daily symptom tracking in patients with fibromyalgia.
METHODOLOGY:
- Researchers conducted the phase 3 PROSPER-FM trial at 25 community sites in the United States to assess the efficacy and safety of digital ACT for patients with fibromyalgia.
- A total of 275 adult patients aged 22-75 years with fibromyalgia were randomly assigned to either the digital ACT group (n = 140) or the active control group (n = 135) for 12 weeks.
- Patients in the digital ACT group received a self-guided, smartphone-delivered program in which they learned and practiced the core ACT skills of acceptance, values, mindfulness, defusion, self as context, and willingness and committed action to build psychological flexibility, while the control group underwent daily symptom tracking and received educational materials.
- The primary endpoint was the response rate on the Patient Global Impression of Change (PGIC) at week 12, which is an indicator of patient well-being.
- The secondary endpoints included changes in the Revised Fibromyalgia Impact Questionnaire (FIQ-R) total score and pain intensity, pain interference, and sleep interference scores.
TAKEAWAY:
- At week 12, 71% of the patients in the digital ACT group responded with a minimally improved or better change in the PGIC response, compared with only 22% of the patients in the control group (P < .0001).
- The digital ACT group showed a significant reduction in the impact of fibromyalgia, with a between-group effect size of d = 0.65 (P < .0001) at week 12. The FIQ-R total score significantly improved within 3 weeks of using the self-guided digital ACT app.
- The use of digital ACT also demonstrated positive effects on the levels of weekly pain intensity (P = .001) and depression (P < .0001), compared with the control group.
- No serious adverse effects related to the app were reported, and both groups demonstrated high rates of adherence, with most (72%) participants in the digital ACT group completing at least 42 sessions.
IN PRACTICE:
“The results found in the study are essential for professionals who care for patients with fibromyalgia as they present a new viable treatment alternative,” Guilherme Torres Vilarino, PhD, Santa Catarina State University, Florianópolis, Brazil, wrote in an accompanying editorial.
SOURCE:
This study was led by R. Michael Gendreau, MD, PhD, Gendreau Consulting, Poway, California. It was published online in The Lancet.
LIMITATIONS:
The study population predominantly consisted of women and White individuals, which may limit the generalizability of the findings to more diverse populations. Additionally, the study was conducted in the United States, and the results may thus not be applicable to other countries with different racial, ethnic, educational, and economic characteristics. The study duration was 12 weeks, and the long-term benefits of digital ACT have not yet been shown.
DISCLOSURES:
This study was funded by Swing Therapeutics. Seven authors declared having stock options and/or receiving salary from Swing Therapeutics. Other authors reported having many ties with several sources, including Swing Therapeutics.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.
Clinical Controversy: Watch-and-Wait or Surgery in Rectal Cancer Near Complete Responders?
Having an ostomy is a dreaded prospect for many patients with rectal cancer.
To defer, and potentially avoid, this life-altering surgery,
About 80% of these patients who have a complete clinical response — a perfectly healed scar where the tumor used to be and other favorable features — can forgo total mesorectal excision and preserve their rectum.
The success of watch-and-wait among complete responders has led some centers to offer the approach in patients with near-complete responses to neoadjuvant chemoradiation.
But watch-and-wait for near-complete clinical responders “is very controversial,” Alan P. Venook, MD, a gastrointestinal oncologist at the University of California, San Francisco (UCSF), told this news organization.
“You sure as hell don’t want to miss a chance to cure a patient,” Dr. Venook said.
A near-complete clinical response essentially means there is no sign of the tumor 8 weeks after total neoadjuvant therapy, but the tumor bed hasn’t completely healed.
The goal of watch-and-wait in this scenario is to give near-complete response lesions time to become complete responses.
But there’s no clear way to predict which tumors will evolve into a clinical complete response.
Recent studies evaluating the conversion rate have reported that anywhere from 39% to about 90% of near-complete responders became complete responders. Some of the variation likely comes down to differences in the clinical stage of patients evaluated in each study as well as the limited number of patients who achieve a near-complete response overall.
Other concerns have emerged that waiting for near-complete responses to become complete leaves extra time for some tumors to metastasize and that tumor regrowth is much higher compared with complete responders.
A recent study found that 13% of near-complete responders who preserved their rectum on watch-and-wait developed distant metastases vs about 5% of long-term complete responders. The study also found that just over half of near-complete responders have tumor regrowth compared with about one in five complete responders.
But even with regrowth, “surgery is still curative,” explained Julio Garcia-Aguilar, MD, PhD, a pioneer of watch-and-wait for rectal cancer.
And overall, around 50%-60% of patients with a near-complete response can avoid surgery and preserve their rectum.
Selecting Patients for Watch-and-Wait
The key to deciding which patients are right for watch-and-wait is to understand how a near-complete clinical response was defined in the OPRA trial, a landmark randomized trial led by Dr. Garcia-Aguilar that helped establish watch-and-wait as an option in rectal cancer.
OPRA defined a near-complete response as no visible tumor but, in the tumor bed, mild erythema, superficial ulceration, minor mucosal abnormality or small nodules, and an irregular mucosa. The criteria also included no palpable tumor with smooth induration or a minor mucosal abnormality on the digital rectal exam.
The National Comprehensive Cancer Network mirrored the definition when, for the first time, it recommended watch-and-wait as an option for near-complete response in its 2023 rectal cancer guidelines. The group also added a few MRI requirements.
UCSF offers the watch-and-wait option to some patients with near-complete responses, but each decision is made on a case-by-case basis by a tumor board considering numerous measures of tumor aggressiveness.
Even then, “we have, in many cases, struggled to figure out what the right choices are,” Dr. Venook said.
For those chosen for watch-and-wait, Dr. Venook noted that UCSF has top-notch surgeons, radiation oncologists, medical oncologists, and pathologists who have the resources to follow patients closely.
For community practices without the resources of a major cancer center, watch-and-wait for near-complete response to rectal cancer “is really asking a lot,” Dr. Venook said.
Dr. Garcia-Aguilar, a colorectal surgeon at Memorial Sloan Kettering Cancer Center in New York City, explained that after years of studying the issue, he is comfortable with watch-and-wait in near-complete responders as long as it’s done carefully and in patients who will comply with ongoing surveillance.
Dr. Garcia-Aguilar explained that, after diagnosing a near-complete response 8 weeks following total neoadjuvant therapy, the patient needs to come back 6 weeks later. At that point, it’s time to assess whether that near-complete response is evolving into a complete response or not evolving into a complete response.
If it’s evolving into a complete response, surveillance continues about every 8 weeks, but if the tumor has stopped responding, “you take [the patient] to the operating room,” Dr. Garcia-Aguilar said.
As for the bigger safety concern — that near clinical complete response tumors will metastasize — Dr. Garcia-Aguilar’s opinion is that micrometastases are probably already there when the rectal cancer is first diagnosed and will manifest themselves “no matter what happens to the primary tumor.”
Because of that, he noted, “I don’t think the risk is very high” when surgery is delayed a few months to give near-complete response patients a chance to keep their rectum.
The way to answer the metastasis question is to do a randomized trial pitting surgery against watch-and-wait in patients with near-clinical complete response rectal cancer.
However, Dr. Garcia-Aguilar doesn’t think that trial will ever happen. Patients won’t allow themselves to be randomized to surgery once they find out they might be able to avoid a permanent ostomy, he said.
Dr. Venook had no disclosures. Dr. Garcia-Aguilar reported personal fees from Medtronic, Johnson & Johnson, and Intuitive Surgical.
A version of this article first appeared on Medscape.com.
Having an ostomy is a dreaded prospect for many patients with rectal cancer.
To defer, and potentially avoid, this life-altering surgery,
About 80% of these patients who have a complete clinical response — a perfectly healed scar where the tumor used to be and other favorable features — can forgo total mesorectal excision and preserve their rectum.
The success of watch-and-wait among complete responders has led some centers to offer the approach in patients with near-complete responses to neoadjuvant chemoradiation.
But watch-and-wait for near-complete clinical responders “is very controversial,” Alan P. Venook, MD, a gastrointestinal oncologist at the University of California, San Francisco (UCSF), told this news organization.
“You sure as hell don’t want to miss a chance to cure a patient,” Dr. Venook said.
A near-complete clinical response essentially means there is no sign of the tumor 8 weeks after total neoadjuvant therapy, but the tumor bed hasn’t completely healed.
The goal of watch-and-wait in this scenario is to give near-complete response lesions time to become complete responses.
But there’s no clear way to predict which tumors will evolve into a clinical complete response.
Recent studies evaluating the conversion rate have reported that anywhere from 39% to about 90% of near-complete responders became complete responders. Some of the variation likely comes down to differences in the clinical stage of patients evaluated in each study as well as the limited number of patients who achieve a near-complete response overall.
Other concerns have emerged that waiting for near-complete responses to become complete leaves extra time for some tumors to metastasize and that tumor regrowth is much higher compared with complete responders.
A recent study found that 13% of near-complete responders who preserved their rectum on watch-and-wait developed distant metastases vs about 5% of long-term complete responders. The study also found that just over half of near-complete responders have tumor regrowth compared with about one in five complete responders.
But even with regrowth, “surgery is still curative,” explained Julio Garcia-Aguilar, MD, PhD, a pioneer of watch-and-wait for rectal cancer.
And overall, around 50%-60% of patients with a near-complete response can avoid surgery and preserve their rectum.
Selecting Patients for Watch-and-Wait
The key to deciding which patients are right for watch-and-wait is to understand how a near-complete clinical response was defined in the OPRA trial, a landmark randomized trial led by Dr. Garcia-Aguilar that helped establish watch-and-wait as an option in rectal cancer.
OPRA defined a near-complete response as no visible tumor but, in the tumor bed, mild erythema, superficial ulceration, minor mucosal abnormality or small nodules, and an irregular mucosa. The criteria also included no palpable tumor with smooth induration or a minor mucosal abnormality on the digital rectal exam.
The National Comprehensive Cancer Network mirrored the definition when, for the first time, it recommended watch-and-wait as an option for near-complete response in its 2023 rectal cancer guidelines. The group also added a few MRI requirements.
UCSF offers the watch-and-wait option to some patients with near-complete responses, but each decision is made on a case-by-case basis by a tumor board considering numerous measures of tumor aggressiveness.
Even then, “we have, in many cases, struggled to figure out what the right choices are,” Dr. Venook said.
For those chosen for watch-and-wait, Dr. Venook noted that UCSF has top-notch surgeons, radiation oncologists, medical oncologists, and pathologists who have the resources to follow patients closely.
For community practices without the resources of a major cancer center, watch-and-wait for near-complete response to rectal cancer “is really asking a lot,” Dr. Venook said.
Dr. Garcia-Aguilar, a colorectal surgeon at Memorial Sloan Kettering Cancer Center in New York City, explained that after years of studying the issue, he is comfortable with watch-and-wait in near-complete responders as long as it’s done carefully and in patients who will comply with ongoing surveillance.
Dr. Garcia-Aguilar explained that, after diagnosing a near-complete response 8 weeks following total neoadjuvant therapy, the patient needs to come back 6 weeks later. At that point, it’s time to assess whether that near-complete response is evolving into a complete response or not evolving into a complete response.
If it’s evolving into a complete response, surveillance continues about every 8 weeks, but if the tumor has stopped responding, “you take [the patient] to the operating room,” Dr. Garcia-Aguilar said.
As for the bigger safety concern — that near clinical complete response tumors will metastasize — Dr. Garcia-Aguilar’s opinion is that micrometastases are probably already there when the rectal cancer is first diagnosed and will manifest themselves “no matter what happens to the primary tumor.”
Because of that, he noted, “I don’t think the risk is very high” when surgery is delayed a few months to give near-complete response patients a chance to keep their rectum.
The way to answer the metastasis question is to do a randomized trial pitting surgery against watch-and-wait in patients with near-clinical complete response rectal cancer.
However, Dr. Garcia-Aguilar doesn’t think that trial will ever happen. Patients won’t allow themselves to be randomized to surgery once they find out they might be able to avoid a permanent ostomy, he said.
Dr. Venook had no disclosures. Dr. Garcia-Aguilar reported personal fees from Medtronic, Johnson & Johnson, and Intuitive Surgical.
A version of this article first appeared on Medscape.com.
Having an ostomy is a dreaded prospect for many patients with rectal cancer.
To defer, and potentially avoid, this life-altering surgery,
About 80% of these patients who have a complete clinical response — a perfectly healed scar where the tumor used to be and other favorable features — can forgo total mesorectal excision and preserve their rectum.
The success of watch-and-wait among complete responders has led some centers to offer the approach in patients with near-complete responses to neoadjuvant chemoradiation.
But watch-and-wait for near-complete clinical responders “is very controversial,” Alan P. Venook, MD, a gastrointestinal oncologist at the University of California, San Francisco (UCSF), told this news organization.
“You sure as hell don’t want to miss a chance to cure a patient,” Dr. Venook said.
A near-complete clinical response essentially means there is no sign of the tumor 8 weeks after total neoadjuvant therapy, but the tumor bed hasn’t completely healed.
The goal of watch-and-wait in this scenario is to give near-complete response lesions time to become complete responses.
But there’s no clear way to predict which tumors will evolve into a clinical complete response.
Recent studies evaluating the conversion rate have reported that anywhere from 39% to about 90% of near-complete responders became complete responders. Some of the variation likely comes down to differences in the clinical stage of patients evaluated in each study as well as the limited number of patients who achieve a near-complete response overall.
Other concerns have emerged that waiting for near-complete responses to become complete leaves extra time for some tumors to metastasize and that tumor regrowth is much higher compared with complete responders.
A recent study found that 13% of near-complete responders who preserved their rectum on watch-and-wait developed distant metastases vs about 5% of long-term complete responders. The study also found that just over half of near-complete responders have tumor regrowth compared with about one in five complete responders.
But even with regrowth, “surgery is still curative,” explained Julio Garcia-Aguilar, MD, PhD, a pioneer of watch-and-wait for rectal cancer.
And overall, around 50%-60% of patients with a near-complete response can avoid surgery and preserve their rectum.
Selecting Patients for Watch-and-Wait
The key to deciding which patients are right for watch-and-wait is to understand how a near-complete clinical response was defined in the OPRA trial, a landmark randomized trial led by Dr. Garcia-Aguilar that helped establish watch-and-wait as an option in rectal cancer.
OPRA defined a near-complete response as no visible tumor but, in the tumor bed, mild erythema, superficial ulceration, minor mucosal abnormality or small nodules, and an irregular mucosa. The criteria also included no palpable tumor with smooth induration or a minor mucosal abnormality on the digital rectal exam.
The National Comprehensive Cancer Network mirrored the definition when, for the first time, it recommended watch-and-wait as an option for near-complete response in its 2023 rectal cancer guidelines. The group also added a few MRI requirements.
UCSF offers the watch-and-wait option to some patients with near-complete responses, but each decision is made on a case-by-case basis by a tumor board considering numerous measures of tumor aggressiveness.
Even then, “we have, in many cases, struggled to figure out what the right choices are,” Dr. Venook said.
For those chosen for watch-and-wait, Dr. Venook noted that UCSF has top-notch surgeons, radiation oncologists, medical oncologists, and pathologists who have the resources to follow patients closely.
For community practices without the resources of a major cancer center, watch-and-wait for near-complete response to rectal cancer “is really asking a lot,” Dr. Venook said.
Dr. Garcia-Aguilar, a colorectal surgeon at Memorial Sloan Kettering Cancer Center in New York City, explained that after years of studying the issue, he is comfortable with watch-and-wait in near-complete responders as long as it’s done carefully and in patients who will comply with ongoing surveillance.
Dr. Garcia-Aguilar explained that, after diagnosing a near-complete response 8 weeks following total neoadjuvant therapy, the patient needs to come back 6 weeks later. At that point, it’s time to assess whether that near-complete response is evolving into a complete response or not evolving into a complete response.
If it’s evolving into a complete response, surveillance continues about every 8 weeks, but if the tumor has stopped responding, “you take [the patient] to the operating room,” Dr. Garcia-Aguilar said.
As for the bigger safety concern — that near clinical complete response tumors will metastasize — Dr. Garcia-Aguilar’s opinion is that micrometastases are probably already there when the rectal cancer is first diagnosed and will manifest themselves “no matter what happens to the primary tumor.”
Because of that, he noted, “I don’t think the risk is very high” when surgery is delayed a few months to give near-complete response patients a chance to keep their rectum.
The way to answer the metastasis question is to do a randomized trial pitting surgery against watch-and-wait in patients with near-clinical complete response rectal cancer.
However, Dr. Garcia-Aguilar doesn’t think that trial will ever happen. Patients won’t allow themselves to be randomized to surgery once they find out they might be able to avoid a permanent ostomy, he said.
Dr. Venook had no disclosures. Dr. Garcia-Aguilar reported personal fees from Medtronic, Johnson & Johnson, and Intuitive Surgical.
A version of this article first appeared on Medscape.com.