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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines how individuals with non-alcoholic fatty liver disease (NAFLD) respond to semaglutide, a medication initially used for diabetes. Researchers aim to understand the impact of feeding on the liver in those with NAFLD and assess whether semaglutide can enhance liver health. The trial includes individuals confirmed to have NAFLD, particularly those with liver fat accumulation, as well as healthy volunteers for comparison. Participants will undergo various tests, receive semaglutide injections, and attend multiple follow-up visits to monitor progress over time. As a Phase 2 trial, this research focuses on evaluating semaglutide's effectiveness in an initial, smaller group, providing participants an opportunity to contribute to significant medical advancements.

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.

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

Research has shown that semaglutide is generally safe for people with non-alcoholic fatty liver disease (NAFLD). In one study, semaglutide lowered liver fat and improved liver health markers. Another study found that it reduced liver stiffness, indicating less liver damage.

Regarding safety, semaglutide has been tested for other conditions and already has FDA approval for certain liver diseases. This approval suggests it is unlikely to cause major harm. However, individuals may experience mild side effects like nausea or an upset stomach. Consulting a healthcare provider about any concerns before joining a trial is always advisable. ^{1 2 3 4 5}

Why are researchers excited about this study treatment for NAFLD?

Most treatments for Non-Alcoholic Fatty Liver Disease (NAFLD) focus on lifestyle changes like diet and exercise, but there aren't many effective medications available. Semaglutide is unique because it is a GLP-1 receptor agonist, which is traditionally used to treat type 2 diabetes by regulating blood sugar levels. Researchers are excited about semaglutide because it has shown promise in reducing liver fat and inflammation, which are key issues in NAFLD. Its potential to improve liver health by targeting the underlying metabolic processes makes it a promising option compared to the limited pharmaceutical treatments currently available.

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

Research has shown that semaglutide effectively treats non-alcoholic fatty liver disease (NAFLD). One study found that semaglutide greatly improved liver enzymes and reduced liver stiffness, both important indicators of liver health. Another study reported that 63% of participants experienced improvement in liver inflammation and damage without worsening liver scarring. Additionally, evidence suggests that semaglutide aids in weight loss, which may further enhance liver health. In this trial, participants with steatosis or NASH will receive semaglutide to evaluate its effects on liver health. Overall, semaglutide shows promise for improving liver health in people with NAFLD. ^{1 2 3 4 6}

Who Is on the Research Team?

Yaron Rotman, M.D.

Principal Investigator

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

Are You a Good Fit for This Trial?

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 have been diagnosed with fatty liver disease through a biopsy or imaging in the last year.

Exclusion Criteria

I am HIV positive.

My thyroid condition is not under control.

I am currently taking orlistat.

Timeline for a Trial Participant

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)

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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 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 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]

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 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]

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]

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. 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 ...

3. 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% ...

4. 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 ...

5. journals.lww.com journals.lww.com/ajg/fulltext/2023/10001/s1485_semaglutide_outcomes_in_non_alcoholic_fatty.2446.aspx

S1485 Semaglutide Outcomes in Non-Alcoholic Fatty Liver... Conclusion: In our cohort, patients with NAFLD on semaglutide had significant improvement in LFT associated with weight loss. More studies with larger sample ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/36934740/

Semaglutide 2·4 mg once weekly in patients with ... - PubMed In patients with NASH and compensated cirrhosis, semaglutide did not significantly improve fibrosis or achievement of NASH resolution versus placebo.