Semaglutide for Non-Alcoholic Fatty Liver Disease

Overseen By Yaron Rotman, M.D.

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Must not be taking: Atypical neuroleptics, Insulin, others

Disqualifiers: Pregnancy, Hepatitis, HIV, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

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: 10

Duration: 30 weeks

84 Participants Needed

Trial Summary

What is the purpose of this trial?

Background: In non-alcoholic fatty liver disease (NAFLD), fat accumulates in the liver and can cause damage. Researchers want to learn what causes the damage NAFLD, and to see if a medication can help. Objective: To find out how the liver in people with NAFLD responds to feeding, and how this relates to their response to the drug semaglutide. Eligibility: People with NAFLD and healthy volunteers ages 18 and older Design: Participants will be screened with: Medical history Physical exam Blood tests Imaging: A machine will take pictures of the participant s body. Within 2-8 weeks of enrollment, participants will stay in the clinic for several days. This includes: Blood, urine, heart, and imaging tests For NAFLD participants only: A needle-like device will remove a small biopsy of the liver and fatty tissue. Participants will be alone in a special room for 5 hours. They will breathe through a tube under the nostrils. They will have blood drawn several times. The baseline visit concludes participation for healthy volunteers but NAFLD participants will contine. About 6 weeks after discharge, participants will stay in the clinic again and repeat the tests. They will get their first semaglutide dose by injection. Participants will have visits weeks 1, 2, 4, 8, 12, 16, 20, and 24 of treatment. Visits include blood tests. Participants will inject semaglutide once a week at home. At week 30, participants will stay in the clinic again and repeat the tests. Participants will have a final visit 12 weeks after stopping treatment. This includes blood and urine tests. ...

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, certain medications, especially those for diabetes or those known to cause fatty liver disease, may need to be stopped or adjusted before enrollment. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the drug semaglutide for treating 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, but as with any medication, there may be side effects, so it's important to discuss with a healthcare provider. ^{2 3 4 6 7}

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

Semaglutide is unique because it not only improves liver health but also helps with weight loss and resolves non-alcoholic steatohepatitis (NASH), which is not achieved by other treatments like obeticholic acid. Additionally, semaglutide is considered safer and more effective in reducing liver fat and improving liver enzymes compared to other available options. ^{2 4 5 6 8}

Research Team

Yaron Rotman, M.D.

Principal Investigator

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Eligibility Criteria

Adults aged 18+ with Non-Alcoholic Fatty Liver Disease (NAFLD) can join this trial. They must have a certain level of liver fat and no recent significant alcohol consumption. Exclusions include pregnancy, breastfeeding, other liver diseases, uncontrolled diabetes or thyroid issues, severe kidney disease, specific medication use within the last 3 months, and inability to undergo MRI or biopsy.

Inclusion Criteria

I have a fatty liver with a fat content of 10% or more.

Ability of subject to understand and the willingness to sign a written informed consent document

I am 18 years old or older.

Exclusion Criteria

I am HIV positive.

My thyroid condition is not under control.

I am currently taking orlistat.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-8 weeks

1 visit (in-person)

Baseline Assessment

Participants undergo initial assessments including blood, urine, heart, and imaging tests. NAFLD participants receive liver and fatty tissue biopsies.

Several days

In-clinic stay

Treatment

Participants receive semaglutide injections weekly for 30 weeks. Visits occur at weeks 1, 2, 4, 8, 12, 16, 20, and 24 for blood tests.

30 weeks

8 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, including a final visit 12 weeks after stopping treatment with blood and urine tests.

12 weeks

1 visit (in-person)

Treatment Details

Interventions

• Semaglutide

Trial Overview The trial is testing how Semaglutide affects the liver's response to sugar in people with NAFLD. Participants will undergo tests including blood work and imaging before and after receiving Semaglutide injections for up to 24 weeks at home followed by additional clinic visits.

Participant Groups

Group I: Arm B: NASH Experimental Treatment 1 Intervention

Participants with NASH on baseline biopsy

Group II: Arm A: Steatosis Experimental Treatment 1 Intervention

Participants with steatosis on baseline biopsy

Group III: Arm C: Healthy Active Control 1 Intervention

Healthy Volunteers

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?

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Lead Sponsor

Trials

2,513

Recruited

4,366,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

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]

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 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]

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

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

4. 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]

5. 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]

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]