GLP-1 RA on Alcohol Consumption, Metabolism and Liver Parameters in Patients With Obesity and Fatty Liver Disease

There is evidence that alcoholic beverage consumption significantly interacts with food energy intake. Furthermore, there is accumulating evidence showing independent, combined, and modifying effects of alcohol and metabolic factors on the onset and progression of chronic liver disease. Preclinical and clinical data have showed that GLP-1 RA can decrease alcohol consumption, particularly in obese patients. Moreover there is evidence that semaglutide can improve the liver sinusoidal milieu in pre-clinical models of cirrhosis.

In this study, the investigators aim to assess if patients treated with semaglutide and receiving counselling will achieve a significantly higher alcohol abstinence compared to patients only receiving counselling.

In Switzerland, approximately 20% of the population is consuming more alcohol than recommended by the WHO. There is evidence that alcoholic beverage consumption significantly interacts with food energy intake. Although several studies have investigated the role of alcohol in obesity, there is still a lack of knowledge about specific roles of different types of alcoholic beverages and on the effect of consumption patterns in patients with metabolic syndrome and obesity. Nevertheless, there is accumulating evidence showing independent, combined, and modifying effects of alcohol and metabolic factors on the onset and progression of chronic liver disease.

Glucagon-like peptide-1 (GLP-1)-based therapy for type 2 diabetes was introduced in 2006. GLP-1 is an incretin hormone, which is secreted from endocrine L cells of the small intestine in response to nutrients in the gut lumen. Exendin-4 binds to the GLP-1R with high affinity and acts as a receptor agonist, thus referred to as GLP-1 receptor agonists (GLP-1 RA). To date the GLP-1 RA: dulaglutide, semaglutide, liraglutide, lixisenatide and exenatide are approved for the treatment of diabetes mellitus type II in Switzerland. Since 2020, the GLP-1 RA semaglutide is also approved for the treatment of obesity in Switzerland. GLP-1 RA have a well-established effect on the food reward system which is regulated by key mesolimbic brain regions, the ventral tegmental area (VTA) and nucleus accumbens (NAc)11. Interestingly, these regions are also involved in the rewarding effects of drugs of abuse and alcohol. A link between alcohol intake and GLP-1 has been demonstrated in several preclinical studies and may play an important role in the development of addiction. The findings are consistent with the hypothesis that systemic administration of GLP-1 RA can influence the mesolimbic dopamine system and reward-seeking behaviours associated with alcohol use disorder (AUD). Furthermore, preclinical data has shown that GLP-1 RA, namely, liraglutide significantly improved liver microvascular function and exhibited anti-fibrotic effects of confirmed in human liver tissue.

In metabolic fatty liver disease, GLP-1 RA have a significant effect on reducing steatosis and inflammation. Obesity is one of the main risk factors for fatty liver disease, particularly central adiposity, and one of the leading drivers for liver disease progression, independent of the cause of liver disease. In a Swiss referral liver centre, 75% of patients with advanced cirrhosis have either alcohol, metabolic or combined factors (25%) as the cause for liver disease. Therapeutic strategies approaching both aetiologies are thus urgently needed.

The investigators aim to investigate in this study, whether there is a significant beneficial effect of GLP-1 RA, specifically semaglutide, on alcohol consumption, specifically in obese patients. Furthermore, the investigators aim to systematically assess drinking patterns and alcohol beverage consumption in patients with obesity assessed with the innovative direct alcohol biomarker phosphatidylethanol (PEth)24 that overcomes the problems of low reliability of medical history, standard questionnaires and previous tests in assessing recent alcohol consumption.

Eligibility Criteria:
Inclusion Criteria:

* BMI ≥ 35 kg/m² OR BMI ≥ 28 kg/m² in the case of weight-related co-morbidities (pre-diabetes or type 2 diabetes mellitus, hypertension, dyslipidemia).
* Fatty liver disease (steatosis on ultrasound and/or CAP value on FS \> 238 dB/m)
* Age 18 - 80 years
* Alcohol Use Disorder Identification Test-C Score \>4 (AUDIT-C) Score ≥4 for women and ≥5 for men (as measured from AUDIT-questionnaire distributed in visit 1)
* Sufficient skills for German or French language (written and spoken)
* Signed informed consent

Exclusion Criteria:

* Active illicit substance use
* AUDIT-score \< 5 (males)/ 4 (females) (as measured from AUDIT-questionnaire distributed in visit 1)
* Current treatment with drugs against alcohol dependence (disulfiram, acamprosate, naltrexone, baclofen and nalmefene)
* Any known contraindication to semaglutide
* Presence or history of a hepatic or extrahepatic malignancy from the previous 6 months