Department of Clinical Medicine, University of Copenhagen
Alcohol use disorder is a major public health problem in large parts of the world including Europe and the USA, imposing a high cost on society and estimated to cause 6% of all deaths . Alcohol use disorder is underdiagnosed and undertreated, and more than 2/3 of patients in abstinence-oriented treatment will relapse within the first year of achieving abstinence. Currently available pharmacotherapies such as disulfiram, naltrexone, acamprosate, and nalmefene have low to moderate efficacy. Thus, there remains a strong need for new molecular targets in the medical treatment of alcohol use disorder.
Glucagon-like peptide-1 (GLP-1)-based therapy has been used in the treatment of type 2 diabetes since 2006. GLP-1 is an incretin hormone secreted from endocrine L-cells of the small intestine. GLP-1 has insulinotropic effects and inhibits glucagon release, which together lower blood glucose levels (Holst 2007). GLP-1 is also produced as a neurotransmitter in the brain and acts centrally to regulate nutrient intake, and GLP-1 receptors are expressed in brain areas involved with reward and addiction, such as the ventral tegmental area and nucleus accumbens in rodents, humans, and non-human primates . The GLP-1 system has therefore attracted interest as a potential target for treating addictions, and GLP-1 receptor agonists have shown promise in reducing alcohol intake in rodents . Human gene variants of the GLP-1 receptor also show an association with the prevalence of AUD and with behavioral and neurological responses to alcohol in human laboratory studies.
Endogenous GLP-1 is degraded within minutes, but GLP-1 analogs with significantly longer half-lives have been developed as diabetes medications. Here, we tested two different clinically used peptide compounds: exenatide, in an extended-release formulation, and liraglutide. Pharmacokinetic properties of the two drugs in humans are summarized in Table 1. Evidence from rodent studies indicates that both exenatide and liraglutide penetrate the brain after systemic administration. In humans, exenatide requires several weeks to reach steady blood levels, and liraglutide requires careful up-titration to reduce side effects such as nausea and vomiting.