Semaglutide for Non-alcoholic Fatty Liver Disease

(SAMARA Trial)

Overseen By Egbert Madamba

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of California, San Diego

Must not be taking: Weight loss medications

Disqualifiers: Excessive alcohol, Cirrhosis, Hepatitis B, others

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 52 weeks

120 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot participate if you have used weight loss medications, including GLP1RA, in the last 90 days.

What data supports the effectiveness of the drug semaglutide for non-alcoholic fatty liver disease?

Research shows that semaglutide can lead to significant weight loss and improve liver health in patients with non-alcoholic fatty liver disease (NAFLD). It is also noted for resolving non-alcoholic steatohepatitis (NASH), a more severe form of NAFLD, making it a promising option for these conditions. ^{1 2 3 4 5}

Is semaglutide safe for humans?

Research shows that semaglutide, used under names like Ozempic, Wegovy, and Rybelsus, has been studied for safety in conditions like non-alcoholic fatty liver disease and diabetes. These studies generally support its safety in humans, though specific side effects and risks should be discussed with a healthcare provider. ^{2 3 5 6 7}

How is the drug semaglutide unique in treating non-alcoholic fatty liver disease?

Semaglutide is unique because it is a glucagon-like peptide-1 (GLP-1) receptor agonist that not only improves liver health by reducing liver fat and enzymes but also promotes significant weight loss, which is beneficial for patients with non-alcoholic fatty liver disease. Unlike other treatments, semaglutide has shown exclusive effectiveness in resolving non-alcoholic steatohepatitis (NASH), a more severe form of the disease. ^{2 3 4 6 8}

What is the purpose of this trial?

Conduct a community intervention study that will 1) validate a screening approach to identify patients at risk for advanced NAFLD in the obese or T2DM population, and 2) test whether semaglutide treatment is effective for the management of significant fibrosis due to NAFLD in high-risk patients.

Research Team

Rohit Loomba

Principal Investigator

University of California, San Diego

Eligibility Criteria

This trial is for adults aged 40-79 with obesity or type 2 diabetes, showing symptoms of diabetes and having a BMI ≥27 kg/m² (or ≥25 kg/m² with pre-diabetes). They must have liver fibrosis due to NAFLD but not severe cirrhosis or other chronic liver diseases. Participants should not be heavy alcohol users, on certain medications, or have had significant weight loss recently.

Inclusion Criteria

My liver tests show significant scarring or stiffness.

I understand the study requirements and have signed the consent form.

My BMI is over 27, or it's over 25 and I have pre-diabetes or type 2 diabetes.

Exclusion Criteria

Your liver stiffness is higher than 20 kilopascals.

Your kidney function is severely reduced, as measured by a specific equation.

I haven't taken any weight loss drugs, including GLP1RA, in the last 90 days.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive semaglutide or placebo for the management of significant fibrosis due to NAFLD

52 weeks

Weekly visits for subcutaneous injections

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Semaglutide

Trial Overview The study aims to identify at-risk individuals for advanced NAFLD and assess the effectiveness of Semaglutide in treating significant fibrosis caused by NAFLD in these high-risk patients. It compares Semaglutide against a placebo in a real-world setting.

Participant Groups

Group I: Semaglutide Experimental Treatment 1 Intervention

2.4 mg weekly for 52 weekly in a 3 ml PDS290 pen-injector containing Semaglutide 3.0 mg/ml for subcutaneous use

Group II: Placebo Placebo Group 1 Intervention

2.4 mg weekly for 52 weekly in a 3 ml PDS290 pen-injector containing 3.0 mg/ml of a placebo solution for subcutaneous use

Semaglutide is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Ozempic for:

• Type 2 diabetes
• Cardiovascular disease
• Obesity

Approved in United States as Ozempic for:

• Type 2 diabetes
• Cardiovascular disease
• Obesity

Approved in Canada as Ozempic for:

• Type 2 diabetes
• Cardiovascular disease
• Obesity

Approved in Japan as Ozempic for:

• Type 2 diabetes
• Cardiovascular disease
• Obesity

Approved in United States as Wegovy for:

• Obesity

Approved in United States as Rybelsus for:

• Type 2 diabetes

Who Is Running the Clinical Trial?

University of California, San Diego

Lead Sponsor

Trials

1,215

Recruited

1,593,000+

Findings from Research

Semaglutide treatment in obese mice led to significant weight loss and improvements in metabolic health, including better glucose tolerance, reduced insulin resistance, and lower liver inflammation, indicating its efficacy as a GLP-1 receptor agonist.

The study found that Semaglutide's benefits on liver health and metabolic markers were not solely due to weight loss, as it also directly improved glucose uptake and reduced endoplasmic reticulum stress, highlighting its potential mechanisms of action beyond just weight reduction.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Obese mice weight loss role on nonalcoholic fatty liver disease and endoplasmic reticulum stress treated by a GLP-1 receptor agonist. Pontes-da-Silva, RM., de Souza Marinho, T., de Macedo Cardoso, LE., et al.[2022]

In a systematic review of 8 studies involving 2413 patients, 24 weeks of semaglutide treatment significantly reduced liver enzymes (alanine transaminase and aspartate transaminase) and improved liver fat content and stiffness, indicating its efficacy in treating non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH).

Despite its benefits, semaglutide treatment was associated with a higher risk of serious gastrointestinal adverse events, such as nausea and vomiting, highlighting the need for careful monitoring of side effects during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Role of semaglutide in the treatment of nonalcoholic fatty liver disease or non-alcoholic steatohepatitis: A systematic review and meta-analysis. Bandyopadhyay, S., Das, S., Samajdar, SS., et al.[2023]

In a phase 2 trial involving 71 patients with NASH-related cirrhosis, semaglutide did not significantly improve liver fibrosis or lead to NASH resolution compared to placebo after 48 weeks.

The safety profile of semaglutide was similar to that of the placebo, with no new safety concerns identified, and common side effects included nausea and diarrhea, but overall liver and kidney function remained stable.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Semaglutide 2·4 mg once weekly in patients with non-alcoholic steatohepatitis-related cirrhosis: a randomised, placebo-controlled phase 2 trial. Loomba, R., Abdelmalek, MF., Armstrong, MJ., et al.[2023]

Semaglutide and obeticholic acid (OCA) both show histological improvement in patients with non-alcoholic fatty liver disease (NAFLD), but only semaglutide leads to complete resolution of non-alcoholic steatohepatitis (NASH).

Semaglutide is considered the safer option, promoting significant weight loss and better outcomes for hepatic steatosis, while OCA can improve NASH-associated fibrosis but may cause side effects like dyslipidemia and severe itching, necessitating caution in certain patient populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparing the Efficacy and Safety of Obeticholic Acid and Semaglutide in Patients With Non-Alcoholic Fatty Liver Disease: A Systematic Review. Ahmed, NR., Kulkarni, VV., Pokhrel, S., et al.[2022]

Semaglutide significantly improves key indicators of non-alcoholic fatty liver disease (NAFLD), including the likelihood of non-alcoholic steatohepatitis (NASH) resolution and reductions in liver stiffness and liver enzymes, based on a meta-analysis of three randomized controlled trials involving 458 patients.

While semaglutide is effective in treating NAFLD and also promotes weight loss and better glycemic control, it does increase gastrointestinal side effects, although the overall risk of serious adverse events remains similar to placebo.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of semaglutide in non-alcoholic fatty liver disease. Zhu, K., Kakkar, R., Chahal, D., et al.[2023]

In a 24-week pilot study involving 16 patients with non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes, oral semaglutide significantly improved liver function, reduced body weight, and lowered triglyceride levels.

The treatment was associated with a decrease in insulin resistance and hepatic steatosis, with most side effects being mild gastrointestinal issues, indicating a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of oral semaglutide in patients with non-alcoholic fatty liver disease complicated by type 2 diabetes mellitus: A pilot study. Arai, T., Atsukawa, M., Tsubota, A., et al.[2022]

In a study of 213 patients with type 2 diabetes, weekly subcutaneous semaglutide significantly reduced biomarkers of metabolic-associated fatty liver disease (MAFLD), specifically the hepatic steatosis index (HSI) and fibrosis-4 (FIB-4) index, over 24 weeks.

The improvements in liver health were primarily linked to weight loss and reductions in triglyceride levels and insulin resistance, indicating that semaglutide's benefits extend beyond just controlling blood sugar levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of semaglutide on fatty liver disease biomarkers in patients with diabetes and obesity. Carretero-Gómez, J., Carrasco-Sánchez, FJ., Fernández-Rodríguez, JM., et al.[2023]

In a review of 37 randomized controlled trials involving patients with non-alcoholic fatty liver disease (NAFLD), semaglutide was found to significantly improve liver enzymes and other health markers, showing a therapeutic advantage over other treatments.

Both liraglutide and dapagliflozin also demonstrated beneficial effects on liver health and metabolic parameters, but semaglutide was highlighted as the most effective option based on high certainty evidence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative efficacy of 5 sodium-glucose cotransporter protein-2 (SGLT-2) inhibitor and 4 glucagon-like peptide-1 (GLP-1) receptor agonist drugs in non-alcoholic fatty liver disease: A GRADE-assessed systematic review and network meta-analysis of randomized controlled trials. Gu, Y., Sun, L., Zhang, W., et al.[2023]

References

1. England pubmed.ncbi.nlm.nih.gov

Obese mice weight loss role on nonalcoholic fatty liver disease and endoplasmic reticulum stress treated by a GLP-1 receptor agonist. [2022]

2. Netherlands pubmed.ncbi.nlm.nih.gov

Role of semaglutide in the treatment of nonalcoholic fatty liver disease or non-alcoholic steatohepatitis: A systematic review and meta-analysis. [2023]

3. Netherlands pubmed.ncbi.nlm.nih.gov

Semaglutide 2·4 mg once weekly in patients with non-alcoholic steatohepatitis-related cirrhosis: a randomised, placebo-controlled phase 2 trial. [2023]

4. United States pubmed.ncbi.nlm.nih.gov

Comparing the Efficacy and Safety of Obeticholic Acid and Semaglutide in Patients With Non-Alcoholic Fatty Liver Disease: A Systematic Review. [2022]

5. United States pubmed.ncbi.nlm.nih.gov

Efficacy and safety of semaglutide in non-alcoholic fatty liver disease. [2023]

6. Australia pubmed.ncbi.nlm.nih.gov

Efficacy and safety of oral semaglutide in patients with non-alcoholic fatty liver disease complicated by type 2 diabetes mellitus: A pilot study. [2022]

7. Spain pubmed.ncbi.nlm.nih.gov

Effect of semaglutide on fatty liver disease biomarkers in patients with diabetes and obesity. [2023]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Comparative efficacy of 5 sodium-glucose cotransporter protein-2 (SGLT-2) inhibitor and 4 glucagon-like peptide-1 (GLP-1) receptor agonist drugs in non-alcoholic fatty liver disease: A GRADE-assessed systematic review and network meta-analysis of randomized controlled trials. [2023]