GLP-1s Hold Promise as Treatment for Alcohol Use Disorder

Alcohol use disorder (AUD) remains a public health problem globally and within the United States, where 8% to 11% of adults meet diagnostic criteria for the disorder.^1,2 AUD is associated with a variety of cardiometabolic comorbidities, alcohol-associated hepatic disease, and increased healthcare service utilization, including emergency department visits and hospitalizations.^3,4

Despite the severity of alcohol-related clinical and functional consequences, few individuals with AUD receive treatment,⁵ with less than 6% being referred for formal treatment² and fewer than 15% receiving treatment during their lifetime.¹ Although 3 medications—acamprosate, disulfiram, and naltrexone—are approved by the Food and Drug Administration (FDA) for the treatment of AUD, and although both acamprosate and naltrexone are recommended in American Psychiatric Association guidelines based on extensive safety and efficacy data,⁶ less than 2% of individuals with AUD are prescribed these medications.⁷

Barriers to treatment include tolerability issues, stigma, and socioeconomic barriers.⁸ In addition, common medical comorbidities in those with AUD might preclude the use of both naltrexone and acamprosate. For example, naltrexone should be used with caution in those with hepatic disease, and acamprosate should be used with caution in those with renal impairment.^9,10  These contraindications and the low prescribing rates for the available FDA-approved AUD medications highlight the need for novel interventions for the treatment of AUD. GLP-1 receptor agonists have emerged as a potential treatment option in this setting.

This article, part 2 in a 3-part series on GLP-1 receptor agonists for the treatment of substance use disorders, reviews the state of the evidence on GLP-1 receptor agonists for AUD.

GLP-1 Receptor Agonists in the Treatment of AUD

Evidence suggests that GLP-1 receptor agonists can be effective in mitigating symptoms of AUD and improving associated clinical outcomes. Over the past 10 years, preclinical evidence has shown the potential of GLP-1 analogs to attenuate alcohol’s ability to activate the mesolimbic dopamine system.^11-13 Although the primary mechanisms through which GLP-1 regulates alcohol-related behaviors are not fully elucidated, genetic variations in genes encoding for the GLP-1 receptor have been identified as being associated with both AUD and at-risk drinking.¹⁴

Over the past several years, there has been an emergence of cohort studies, clinical trials, systematic reviews, and meta-analyses examining the safety, efficacy, and clinical outcomes of GLP-1 receptor agonists in the treatment of AUD.

In an observational cohort study examining outcomes related to alcohol-associated hospitalizations in 227,866 individuals with AUD exposed to GLP-1 receptor agonists, semaglutide and liraglutide were associated with a lower risk for alcohol-related hospitalization than acamprosate, disulfiram, and naltrexone.¹⁵

A registry-based cohort and self-controlled case series study of 38,454 patients examined the effect of GLP-1 receptor agonists on the risk of alcohol-related events (alcohol-related hospitalizations, use of medications for AUD, and use of medications for alcohol withdrawal).¹⁶ In this study, the use of GLP-1 receptor agonists was associated with a lower risk for an alcohol-related event (hazard ratio [HR], 0.46; 95% CI, 0.24-0.86) relative to dipeptidyl peptidase-4 inhibitors, another type of medication used for diabetes that prevents the breakdown of GLP-1.

In a recent phase 2, double-blind, parallel-arm trial, 48 participants were randomized to receive weekly doses of semaglutide or placebo.¹⁷ Although semaglutide did not affect the average number of drinks per calendar day or drinking days, it significantly reduced the number of drinks per drinking day (P = 0.04), weekly alcohol cravings (P = 0.01), and the amount of alcohol consumed, with medium to large effect sizes for reduction in grams of alcohol consumed (P = 0.01).

A recent systematic review examined the association between GLP-1 receptor agonist use and change in alcohol consumption in 6 studies with 88,190 participants; 44% (n = 38,740) received GLP-1 receptor agonists.¹⁸ The authors noted that although multiple observational studies demonstrated fewer alcohol-related adverse events and a reduction in alcohol use with GLP-1 receptor agonists relative to placebo, there is less high-quality evidence supporting these agents for AUD at this time. One randomized controlled trial did not demonstrate a reduction in alcohol consumption with exenatide versus placebo, but in a secondary analysis of another randomized controlled trial, those taking dulaglutide were 29% more likely to reduce alcohol intake than those given placebo (relative effect size 0.71; 95% CI 0.52-0.97; P=0.04).^19,20

Additional systematic and scoping reviews have examined the potential role of GLP-1 receptor agonists in the treatment of multiple substance use disorders, but these reviews provide an incomplete review of the existing literature on AUD.^21,22

Clinical trials examining the efficacy of GLP-1 receptor agonists in treating alcohol use are ongoing, and the results of these trials will further inform clinical practice.²³

Conclusion

AUD is not only widely prevalent but also costly and associated with a variety of adverse health and psychosocial outcomes.²⁴ Healthcare providers should be cognizant of screening methods for AUD to better identify individuals who might benefit from treatment. In addition, healthcare providers should be aware of evidence-based treatment options for AUD. There are a variety of FDA-approved medications for AUD, but many patients with AUD remain refractory to treatment despite the use of psychotherapies and FDA-approved medications. Thus, additional treatment options are needed for AUD, and while still off-label, GLP-1 receptor agonists have emerged as a potential option in this setting. Healthcare providers should stay abreast of the current evidence surrounding this topic and can implement GLP-1 receptor agonists into their clinical practice when appropriate. Having additional treatment options to manage the complexities of AUD will serve to improve outcomes and quality of life for those living with AUD.

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This article originally appeared on Clinical Advisor