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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Semaglutide Arm | Experimental | Patients assigned to this arm will be treated with semaglutide and standard of care for weight reduction (nutritional and exercise recommendations) for 16 weeks. |
|
| Control Arm | Active Comparator | Patients assigned to this arm will be treated with standard of care for weight reduction (nutritional and exercise recommendations) for 16 weeks. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Semaglutide | Drug | Treatment with semaglutide, following standard clinical practice as per below schedule: Week 1-4: Injected dose of 0,25 mg i.d. Week 5-8: Injected dose of 0,5 mg i.d. Week 9-12: Injected dose of 1,0 mg i.d. Week 13-16: Injected dose of 1,7 mg i.d. After week 16: Injected dose of 2,4 mg i.d. |
| Measure | Description | Time Frame |
|---|---|---|
| Proportion of patients achieving total alcohol abstinence (measured by negative PEth test) | Percentage of patients achieving total alcohol abstinence from baseline to follow-up after 16 weeks of treatment, measured by negative PEth test, in patients treated with semaglutide vs control. | From inclusion date (baseline) until end of the study, total duration 16 weeks per patient |
| Measure | Description | Time Frame |
|---|---|---|
| Proportion of patients achieving total alcohol abstinence (measured by TFLB method) | Percentage of patients achieving total alcohol abstinence from baseline to follow-up after 16 weeks of treatment, measured by TFLB method, in patients treated with semaglutide vs control. | From inclusion date (baseline) until end of the study, total duration 16 weeks per patient |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Susana Gomes Rodrigues, MD | Contact | +41 31 632 59 54 | susana.gomesrodrigues@insel.ch |
| Name | Affiliation | Role |
|---|---|---|
| Susana Gomes Rodrigues, MD | University Hospital Bern (Inselspital), Hepatology | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University Hospital Bern | Bern | 3010 | Switzerland |
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This is an exploratory, monocentric, randomized controlled clinical trial
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No blinding procedures in place
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| Weight reduction recommendations (nutritional and exercise) | Behavioral | Participants will receive nutritional and exercise recommendations and 2 telephone consultations |
|
| Proportion of patients maintaining total alcohol abstinence (measured by negative EtG) | Percentage of patients maintaining total alcohol abstinence from baseline to follow-up after 16 weeks of treatment, measured by negative EtG in patients treated semaglutide vs. control | From inclusion date (baseline) until end of the study, total duration 16 weeks per patient |
| Change of alcohol abstinent days (cumulative abstinent days, by TFLB method) | Assessment of change in percentage of alcohol abstinent days after treatment compared to before treatment with semaglutide vs. control (measured by TFLB method) | From inclusion date (baseline) until end of the study, total duration 16 weeks per patient |
| Change of heavy drinking days (by TFLB method) | Assessment of change in percentage of heavy drinking days after treatment compared to before treatment with semaglutide vs. control (measured by TFLB method) | From inclusion date (baseline) until end of the study, total duration 16 weeks per patient |
| Change of total number of drinks per week (by TFLB method) | Assessment of change in percentage of total number of drinks per week after treatment compared to weeks before treatment with semaglutide vs. control (measured by TFLB method) | From inclusion date (baseline) until end of the study, total duration 16 weeks per patient |
| Pre and post treatment comparison of total abstinence (PEth test) | Change from baseline in number of patients with total alcohol abstinence as assessed by PEth test. | From inclusion date (baseline) until end of the study, total duration 16 weeks per patient |
| Pre and post treatment comparison of total abstinence (assessed by TFLB method) | Change from baseline in number of patients with total alcohol abstinence as assessed by TFLB method. | From inclusion date (baseline) until end of the study, total duration 16 weeks per patient |
| Pre and post treatment comparison of total abstinence (measured by negative EtG) | Change from baseline in number of patients with total alcohol abstinence measured by negative EtG. | From inclusion date (baseline) until end of the study, total duration 16 weeks per patient |
| Pre and post treatment comparison of cumulative abstinent days (by TFLB method) | Change from baseline in number of cumulative abstinent days per patient (measured by TFLB method). | From inclusion date (baseline) until end of the study, total duration 16 weeks per patient |
| Pre and post treatment comparison of drinking days (by TFLB method) | Change from baseline in number of drinking days per patient (measured by TFLB method). | From inclusion date (baseline) until end of the study, total duration 16 weeks per patient |
| Pre and post treatment comparison of number of drinks per week (by TFLB method) | Change from baseline in number of drinks per week per patient (measured by TFLB method). | From inclusion date (baseline) until end of the study, total duration 16 weeks per patient |
| Effects of semaglutide on reward and relief drinking behavior | Assessments of effects of semaglutide on reward and relief drinking behavior (assessed with the Alcohol Expectancy Questionnaire, both study arms). | From inclusion date (baseline) until end of the study, total duration 16 weeks per patient |
| Percentage reduction in transient liver elastography levels assessed by Fibroscan | Percentage reduction in transient liver elastography levels by vibration controlled transient elastography (Fibroscan) from baseline until after 16 weeks of therapy (both study arms). | From inclusion date (baseline) until end of the study, total duration 16 weeks per patient |
| Percentage reduction in transient liver elastography levels assessed by FIB-4 score | Percentage reduction in transient liver elastography levels by FIB-4 score (fibrosis assessment including age, AST, ALT and platelet count) from baseline until after 16 weeks of therapy (both study arms). | From inclusion date (baseline) until end of the study, total duration 16 weeks per patient |
| Percentage reduction in metabolic markers | Percentage reduction in metabolic markers (both study arms): body weight, BMI, fasting glucose, homeostatic model assessment of insulin resistance (HOMA-IR), HbA1c levels from baseline until 16 weeks after therapy | From inclusion date (baseline) until end of the study, total duration 16 weeks per patient |
| Safety profile of semaglutide in described population | Number and description of SAE's concerning semaglutide in described population (semaglutide arm only). | From inclusion date (baseline) until end of the study, total duration 16 weeks per patient |
| Effect of GLP-1 RA therapy on TMA/TMAO pathway | Statistically significant % reduction of TMAO levels (measured by blood test at baseline and after 16 weeks of therapy, semaglutide arm only). | From inclusion date (baseline) until end of the study, total duration 16 weeks per patient |
| ID | Term |
|---|---|
| D009765 | Obesity |
| D005234 | Fatty Liver |
| D000437 | Alcoholism |
| ID | Term |
|---|---|
| D050177 | Overweight |
| D044343 | Overnutrition |
| D009748 | Nutrition Disorders |
| D009750 | Nutritional and Metabolic Diseases |
| D001835 | Body Weight |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D008107 | Liver Diseases |
| D004066 | Digestive System Diseases |
| D019973 | Alcohol-Related Disorders |
| D019966 | Substance-Related Disorders |
| D064419 | Chemically-Induced Disorders |
| D001523 | Mental Disorders |
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| ID | Term |
|---|---|
| C000591245 | semaglutide |
| D015444 | Exercise |
| ID | Term |
|---|---|
| D009043 | Motor Activity |
| D009068 | Movement |
| D009142 | Musculoskeletal Physiological Phenomena |
| D055687 | Musculoskeletal and Neural Physiological Phenomena |
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