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Drs Akshay Jain and Lorenzo Leggio discuss GLP-1 RA therapy and its potential to mitigate alcohol misuse syndrome. https://www.staging.medscape.com/viewarticle/glp-1-ra-therapy-alcohol-use-disorder-2024a1000fur?src=soc_yt --TRANSCRIPT-- 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. 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? 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 in 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. 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? 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. Transcript in its entirety can be found by clicking here: https://www.staging.medscape.com/viewarticle/glp-1-ra-therapy-alcohol-use-disorder-2024a1000fur?src=soc_yt