A better understanding of exenatide can help increase our knowledge of GLP-1 analogues and their possible role in treating addiction.
While exenatide (Byetta) has been discontinued in Australia, we thought reading something different about glucagon-like peptide-1 (GLP-1) analogues – that is, other than shortages and supply chain issues – would be a welcome reprieve. As such, this particular old drug/new indication may seem a little like déjà vu, since we reported on spironolactone for alcohol use disorder not so long ago.1
GLP-1 analogues are indicated for the management of type 2 diabetes,2 and are of course well known for their off-label use for weight loss. As analogues of GLP-1, they ‘increase glucose-dependent insulin secretion, and suppress inappropriate glucagon secretion. They also delay gastric emptying, which slows glucose absorption, and decrease appetite.’2
There has been interest in medicines which regulate appetite (e.g. GLP-1 analogues) for their potential benefits with addiction management.3 This is because the reward pathways activated by food are the same as those associated with drugs and alcohol.3
Alcohol use disorder represents a significant burden of disease, and 40% of those treated reportedly relapse within the first 3 years.3 Management of alcohol use disorder is mainly supportive and focused on counselling and behavioural therapies. Pharmacological options may improve the chances of maintaining abstinence, but are relatively ineffective when used alone. The only approved medicines include acamprosate (reduces neuronal hyperexcitability characteristic of alcohol withdrawal); naltrexone (opioid antagonist and blocks pleasurable effects caused by endogenous opioids released after alcohol intake); and disulfiram (blocks the usual metabolism of alcohol by aldehyde dehydrogenase, which causes unpleasant effects after alcohol consumption).4
The GLP-1 receptors have been of interest as they are expressed in areas of the brain associated with reward and addiction, and animal studies in rodents and non-human primates have reported benefits with reducing alcohol intake and decreasing relapse-like alcohol drinking.3 A randomised, double- blinded, placebo-controlled trial evaluated the impact of once-weekly exenatide (2 mg) in addition to standard cognitive behavioural therapy on the primary endpoint of reducing the number of heavy drinking days in people seeking treatment for alcohol use disorder.3
A total of 127 people were enrolled,with 58 completing the entire trial of 26 weeks’ treatment. Overall, the exenatide group (n = 62) did not significantly reduce the number of heavy drinking days compared to the placebo (n = 65).
Nevertheless, brain scans of a subgroup of participants found exenatide reduced functional MRI (fMRI) alcohol cue reactivity in parts of the brain crucial for reward in addiction, and single-photon emission CT (SPECT) revealed lower dopamine transporter availability, which is important as ‘brain dopamine homeostasis changes following chronic alcohol intake’, and dopamine is important in reward pathways.3
Further exploratory analysis found exenatide, compared to placebo, significantly reduced heavy drinking days by 23.6 percentage points (95% Confidence Interval (CI), –44.4 to –2.7,p = 0.034) and reduced total alcohol intake per 30 days by 1,205 g (95% CI, –2,206 to –204, p= 0.026) in people with BMI >30kg/m2. Exenatide use in the subgroup BMI <25 kg/m2 significantly increased heavy drinking days by 27.5 percentage points (95% CI, 4.7 to 50.2, p = 0.024), but did not reduce total alcohol intake.3
While exenatide treatment overall did not produce significant improvements in the primary endpoint of this study, the preliminary brain scan results and further exploratory analyses appear promising. More research is required to better understand the mechanism for these benefits, and its clinical utility e.g. in people with different severity criteria of alcohol use disorder and different BMIs. Certainly, further investigating is also needed on some of the secondary endpoints, which at times returned mixed results.3 Building on this knowledge about the role of GLP-1 analogues will no doubt help to explore more treatment options in alcohol use disorder and addiction.
- Lau E, Nissen L. Spironolactone for alcohol use disorder. Australian Pharmacist 2023;42(1):56–7.
- Australian Medicines Handbook. Australian Medicines Handbook – Glucagon-like peptide‑1 analogues: Australian Medicines Handbook Pty Ltd; 2023.
- Klausen M, Jensen M, Møller M, et al. Exenatide once weekly for alcohol use disorder investigated in a randomized, placebo-controlled clinical trial. JCI Insight 2022;7(19):e159863.
- Australian Medicines Handbook. Australian Medicines Handbook – Long-term treatment for alcohol dependence: Australian Medicines Handbook Pty Ltd; 2023.