Once weekly semaglutide injections reduced alcohol consumption in patients with alcohol use disorder (AUD) and comorbid obesity.

Results of the randomized controlled trial (RCT), the first, to the authors’ knowledge, to evaluate the GLP-1 receptor agonist (GLP-1RA) semaglutide in patients seeking treatment for AUD who had comorbid obesity also showed significant effects on multiple alcohol-related outcomes.

“These data, when added to the growing evidence, demonstrate the potential of GLP-1RAs as a novel treatment for alcohol use disorder,” the investigators, led by Mette Kruse Klausen, MD, Copenhagen University Hospital in Copenhagen, Denmark, wrote.

“However,” they added, “corroboration with larger RCTs in nonobese patients is needed to address its generalizability.”

The findings were published online on April 30 in The Lancet.

Urgent Need for Treatment Options

AUD is a chronic brain disorder characterized by impaired control over drinking and compulsive alcohol use. Despite decades of research, only three medications — disulfiram, acamprosate, and naltrexone — have been approved by the FDA for AUD, underscoring the urgent need for more effective treatments.

GLP-1RAs, which are approved for the treatment of diabetes and obesity, have gained wide attention for their effects on reward pathways and appetite regulation, suggesting potential use for lessening alcohol consumption. They are generally well tolerated and have a favorable safety profile.

Given growing evidence that GLP-1RAs may influence brain reward pathways involved in addiction, investigators evaluated semaglutide as a potential treatment for AUD.

The new single-center, double-blind study included 108 adults with obesity (BMI ≥ 30) and AUD (Alcohol Use Disorders Identification Test score > 15 and at least six heavy drinking days per month) who were seeking help to reduce or stop alcohol use. About 49% of participants were women, and the mean age of the study population was 52.3 years.

At baseline, participants reported a mean of 17.2 heavy drinking days over the preceding 30 days, and 85% met criteria for severe AUD. They were randomized to receive once weekly subcutaneous semaglutide (titrated up to 2.4 mg) or placebo for 26 weeks.

Throughout the study, participants were also offered up to 10 sessions of cognitive behavioral therapy focused on motivation, craving, and relapse prevention.

The primary endpoint was reduction in the number of heavy drinking days. A total of 81% of participants completed the trial.

At week 26, the mean change in heavy drinking days was -41.1 percentage points (95% CI, -48.7 to -33.5) for the semaglutide group vs -26.4 percentage points (95% CI, -34.1 to -18.6) for the placebo group, corresponding to a mean difference of -13.7 percentage points (95% CI, -22.0 to -5.4; P = .0015).

Patients receiving semaglutide also had greater improvements in secondary outcomes, including total alcohol consumption, number of drinks per drinking day, alcohol craving, and alcohol exposure biomarkers, than those in the placebo group.

Metabolic measures also improved, with greater weight loss observed in the semaglutide group than in the placebo group (-11.2 kg vs -2.2 kg).

AUD a Potential New Indication?

The findings, the authors noted, support a potential expansion of semaglutide’s indications, which could affect “millions of individuals given the global burden of alcohol use disorder and comorbid obesity.”

The most common adverse events were gastrointestinal symptoms such as nausea, loss of appetite, vomiting, abdominal pain, reflux, and constipation, with a higher incidence in the semaglutide group than in the placebo group. These side effects were mainly mild to moderate and transient.

Four serious adverse events were reported — one in the semaglutide group and three in the placebo group — but all had resolved by the 5-week post-trial follow-up, as had all other adverse events.

The precise mechanisms of GLP-1RAs remain incompletely understood, but current evidence suggests they act through overlapping neurobiological and peripheral pathways that influence both metabolic regulation and reward processes implicated in obesity and AUD.

The investigators noted that the study included only participants with a BMI of ≥ 30, limiting the generalizability of the findings. They also cited the lack of alcohol-related follow-up beyond 26 weeks, and the predominantly White study population as additional limitations.

The findings support GLP-1s as a potential novel treatment approach for AUD, the investigators noted. However, they emphasized the need for further studies.

Timely, Compelling Data

In an accompanying editorial with first author Christian S. Hendershot, Department of Population and Public Health Sciences, University of Southern California, Los Angeles, said the study presents “timely and compelling data” indicating the efficacy of semaglutide for AUD.

They also highlighted the relatively low number needed to treat which was 4.3, suggesting the drug could offer efficacy comparable to, or potentially greater than, currently available medications for AUD.

“Should forthcoming studies confirm efficacy of GLP-1 therapies for alcohol use disorder across a broad range of populations and settings, public health implications could be substantial — a possibility that deserves celebration,” the editorialists note.

The study received funding from the Research Foundation, Mental Health Services (Capital Region of Denmark), Novo Nordisk Foundation, Novavi Foundation, Hartmann Foundation, and the Augustinus Foundation. Disclosure information for study and commentary authors is available in the original study publications.