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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether semaglutide, a medication, can manage liver damage in individuals with non-alcoholic fatty liver disease (NAFLD) who are at high risk due to obesity or type 2 diabetes. The study compares semaglutide with a placebo to determine its effect on reducing liver fibrosis (scarring). Participants should have a BMI of 27 or higher, or a BMI of 25 or higher with pre-diabetes or type 2 diabetes, and a diagnosis of significant liver fibrosis. As a Phase 2 trial, this research focuses on assessing the treatment's effectiveness in an initial, smaller group of people.

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.

Is there any evidence suggesting that semaglutide is likely to be safe for humans?

Research has shown that semaglutide is generally safe for individuals with non-alcoholic fatty liver disease (NAFLD). Studies have found that semaglutide can improve liver health without causing major side effects. Specifically, one study found that 36.8% of patients experienced reduced liver scarring with semaglutide, and most participants tolerated it well.

Although semaglutide is not yet approved specifically for NAFLD, it is already approved for treating diabetes and obesity, indicating its safety for these conditions. While more research is needed to fully understand its effects on liver disease, studies so far consider semaglutide to be safe. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for NAFLD?

Unlike the standard treatments for non-alcoholic fatty liver disease, which often focus on lifestyle changes and managing symptoms, Semaglutide offers a novel approach by targeting the GLP-1 receptor. This is the same mechanism that makes it effective for controlling blood sugar levels in diabetes and promoting weight loss. Researchers are excited because Semaglutide's ability to reduce liver fat could potentially address the root cause of the disease rather than just managing its symptoms, offering a new hope for patients with this condition.

What evidence suggests that semaglutide might be an effective treatment for NAFLD?

Research has shown that semaglutide, which participants in this trial may receive, may help treat non-alcoholic fatty liver disease (NAFLD). One study found that 36.8% of patients who took semaglutide had less liver scarring, compared to 22.4% in a group that did not take it. Other studies have found that semaglutide can improve liver health by lowering certain liver enzymes and reducing liver stiffness. It also appears to help with weight and blood fat levels. While these results are promising, more research is needed to understand its long-term effects. ^{1 2 3 6 7}

Who Is on the Research Team?

Rohit Loomba

Principal Investigator

University of California, San Diego

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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 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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10600803/

Efficacy and safety of semaglutide in non-alcoholic fatty liver ... Semaglutide is effective in the treatment of NAFLD while maintaining a well-tolerated safety profile. Future studies are required to evaluate its effects.

2. nejm.org nejm.org/doi/full/10.1056/NEJMoa2413258

Phase 3 Trial of Semaglutide in Metabolic Dysfunction– ... A reduction in liver fibrosis without worsening of steatohepatitis was reported in 36.8% of the patients in the semaglutide group and in 22.4% ...

3. sciencedirect.com sciencedirect.com/science/article/abs/pii/S1871402123001455

Role of semaglutide in the treatment of nonalcoholic fatty ... Treatment with 24 weeks of semaglutide could significantly improve liver enzymes, reduce liver stiffness, and improve metabolic parameters in patients with ...

4. gut.bmj.com gut.bmj.com/content/74/Suppl_3/A233.3.full

IDDF2025-ABS-0014 Effectiveness of semaglutide in non ... Conclusions Our meta-analysis of randomized controlled trials reveals that semaglutide did not significantly improve liver fibrosis, stiffness and steatosis ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11354027/

Therapeutic Effects of Semaglutide on Nonalcoholic Fatty ... Results: There was a substantial improvement in lipid profile, liver enzymes, and body mass index, especially in group II. As for HDL, only ...

6. fda.gov fda.gov/drugs/news-events-human-drugs/fda-approves-treatment-serious-liver-disease-known-mash

FDA Approves Treatment for Serious Liver Disease Known ... Interim results showed 63% of participants receiving Wegovy had MASH resolution and no worsening of liver scarring compared to 34% of ...

7. journals.lww.com journals.lww.com/ajg/fulltext/2023/10001/s1562_efficacy_and_safety_of_semaglutide_in.2523.aspx

S1562 Efficacy and Safety of Semaglutide in Nonalcoholic... Semaglutide demonstrated significant improvements in NASH resolution and NAFLD Activity Score components, but not in fibrosis stage.