Metabolic Surgery for Non-Alcoholic Fatty Liver Disease

(FLAMES Trial)

Recruiting at 23 trial locations

Overseen By Awwab F Hammad, MD

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: Ali Aminian

Must not be taking: Semaglutide, Tirzepatide, Liraglutide, others

Disqualifiers: Chronic liver diseases, Type 1 diabetes, 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 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 4

Duration: 104 weeks

120 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial investigates the effects of metabolic surgery versus medication on metabolic dysfunction-associated steatotic liver disease (MASLD), a condition linked to obesity and diabetes. The researchers aim to determine whether surgery or medication more effectively improves liver health and reduces the risk of further complications. Participants will be divided into two groups: one undergoing metabolic surgery, a type of weight-loss surgery, and the other using specific weight-loss medications, such as incretin-based therapy. Ideal candidates have been diagnosed with MASH (a more severe form of MASLD), have stable weight, and are eligible for metabolic surgery. As a Phase 4 trial, the treatment is already FDA-approved and proven effective, and the trial seeks to understand how it benefits more patients.

Do I need to stop my current medications to join the trial?

The trial does not specify if you need to stop all current medications, but you cannot have taken certain medications like semaglutide, tirzepatide, or liraglutide within 90 days before the study. If you have type 2 diabetes, you should have been on a stable dose of your anti-diabetic medication for at least 3 months before joining.

What is the safety track record for these treatments?

A previous study linked weight-loss surgery, also known as bariatric surgery, to an 88% lower risk of liver problems such as cirrhosis and liver cancer. This surgery aids individuals with fatty liver disease in losing weight and improving liver health. It also reduces the risk of serious heart issues and decreases the chance of dying from any cause.

Research has shown that treatments based on incretin can reduce liver fat and improve liver health in people with fatty liver disease. These treatments, including drugs like liraglutide, semaglutide, and tirzepatide, also assist with weight loss and better control of blood sugar levels.

Both treatment options have been well-tolerated in studies, offering benefits such as improved liver health and reduced risks of other serious health conditions. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Researchers are excited about these treatments for non-alcoholic fatty liver disease (NAFLD) because they explore new avenues beyond traditional lifestyle changes and medications. Metabolic surgery, which includes procedures like Roux-en-Y Gastric Bypass and Sleeve Gastrectomy, is unique because it may not only aid in weight loss but also directly impact metabolic processes that contribute to liver health. On the other hand, incretin-based therapies, using medications like liraglutide, semaglutide, or tirzepatide, target hormones that regulate insulin and appetite, offering a non-surgical alternative. Both approaches focus on underlying metabolic dysfunctions, potentially offering more comprehensive benefits for NAFLD patients than current treatments.

What evidence suggests that this trial's treatments could be effective for MASLD?

This trial will compare metabolic surgery with incretin-based therapy for treating non-alcoholic fatty liver disease. Research has shown that metabolic surgery can significantly improve conditions like MASLD, a liver disease linked to metabolic issues. Studies have found that this surgery can reduce the risk of the liver worsening into more serious diseases, such as cirrhosis and liver cancer, by up to 88%. It can also lower the chances of major heart problems and death. Meanwhile, incretin-based therapies, such as GLP-1 receptor agonists, have shown promise in reducing liver fat and improving liver health. These therapies help by controlling blood sugar and aiding weight loss. Both treatments have been associated with better liver health, offering hope for those with liver disease. ^{1 2 3 4 6}

Who Is on the Research Team?

Ali Aminian, MD

Principal Investigator

The Cleveland Clinic

Are You a Good Fit for This Trial?

This trial is for individuals with MASLD, a liver condition linked to obesity and diabetes. It's open to those who have evidence of liver fibrosis (stages F1-F4). Participants must consent to a liver biopsy if they haven't had one recently.

Inclusion Criteria

Has a negative urine pregnancy test at the first and at the randomization visits for women of childbearing potential

Self-reported stable weight in 3 months before the first study visit (no weight change >5% within 3 months prior to the first study visit)

I am willing and able to join the study and follow its procedures.

Exclusion Criteria

Anemia defined as hemoglobin less than 9 g/dL

Previous participation in this trial and got randomized to one of the study groups but did not proceed

Platelet count <100,000

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Baseline Assessment

Participants undergo baseline liver biopsy and other assessments

1-2 weeks

1 visit (in-person)

Treatment

Participants are randomized to either metabolic surgery or incretin-based therapies for 2 years

104 weeks

Regular visits as per treatment protocol

Follow-up

Participants are monitored for safety and effectiveness after treatment, including a repeat liver biopsy

4 weeks

2 visits (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Incretin-Based Therapy
• Metabolic Surgery

Trial Overview The study compares metabolic surgery against medical treatments using incretin-based therapies for MASH. About 120 patients will be randomly assigned to either the surgery or medication group and tracked over two years, including repeat liver biopsies.

How Is the Trial Designed?

Group I: Metabolic Surgery Active Control 1 Intervention

FLAMES will examine the class effect (not the specific procedure effect) of metabolic surgery. The study is not intended to compare Roux-en-Y Gastric Bypass (RYGB) vs Sleeve Gastrectomy (SG) head-to-head. RYGB and SG constitute one group as a metabolic surgery group. Assignment of RYGB or SG is not based on a randomized design. Each patient and surgical team will make a shared decision about the most appropriate surgical procedure.

Group II: Incretin-Based Therapy Active Control 1 Intervention

Three incretin-based medications that have been approved for treatment of obesity including liraglutide, semaglutide, or tirzepatide will be used in the nonsurgical group. The FLAMES will examine the class effect (not the specific drug effect) of incretin-based therapies. The study is not intended to compare semaglutide vs tirzepatide vs liraglutide head-to-head.

Metabolic Surgery is already approved in European Union, United States for the following indications:

Approved in European Union as Metabolic Surgery for:

• Metabolic Dysfunction-Associated Steatohepatitis (MASH)
• Non-Alcoholic Fatty Liver Disease (NAFLD)
• Liver Fibrosis

Approved in United States as Metabolic Surgery for:

• Metabolic Dysfunction-Associated Steatohepatitis (MASH)
• Non-Alcoholic Fatty Liver Disease (NAFLD)
• Liver Fibrosis

Who Is Running the Clinical Trial?

Ali Aminian

Lead Sponsor

Trials

4

Recruited

4,500+

Sobia Laique, MD

Collaborator

Published Research Related to This Trial

Bariatric surgery in patients with liver cirrhosis is associated with a higher risk of complications and perioperative mortality, based on a review of 11 studies.

Surgeons should proactively discuss the potential for undiagnosed cirrhosis in bariatric surgery patients and establish a plan for management if cirrhosis is discovered during surgery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Systematic Review of Bariatric Surgery in Patients with Liver Cirrhosis. Jan, A., Narwaria, M., Mahawar, KK.[2018]

The term non-alcoholic fatty liver disease (NAFLD) has been updated to metabolic dysfunction-associated fatty liver disease (MAFLD) to better reflect its connection with metabolic syndrome, particularly in obese individuals.

Bariatric and metabolic surgery is emerging as a key treatment strategy for MAFLD, showing promising outcomes in improving liver health from early stages like hepatic steatosis to more severe conditions such as cirrhosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bariatric Surgery and Metabolic Dysfunction-Associated Fatty Liver Disease: a 2022 Update. Lazaridis, II., Delko, T.[2023]

Bariatric surgery, particularly Roux-en-Y gastric bypass (RYGB), significantly improves non-alcoholic fatty liver disease (NAFLD) as evidenced by reduced liver stiffness and improved fibrosis scores in a study of 100 patients over a median follow-up of 12.5 months.

The study found that improvements in liver health were not directly correlated with weight loss, suggesting that bariatric surgery may have specific benefits for liver health beyond just reducing body weight.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bariatric Surgery as an Efficient Treatment for Non-Alcoholic Fatty Liver Disease in a Prospective Study with 1-Year Follow-up : BariScan Study. Nickel, F., Tapking, C., Benner, L., et al.[2019]

In a study of 60 obese patients after mini gastric bypass surgery, a tailored probiotic and micronutrient mixture significantly improved liver health markers, including serum aspartate aminotransferase (ASAT) and NAFLD fibrosis score, compared to a basic micronutrient supplement.

While there was no significant change in serum alanine aminotransferase (ALAT) levels between the two groups, the probiotic and micronutrient combination also reduced serum triglycerides and visceral fat, suggesting a beneficial effect on overall metabolic health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Specifically Tailored Multistrain Probiotic and Micronutrient Mixture Affects Nonalcoholic Fatty Liver Disease-Related Markers in Patients with Obesity after Mini Gastric Bypass Surgery. Crommen, S., Rheinwalt, KP., Plamper, A., et al.[2023]

Bariatric surgery, specifically sleeve gastrectomy, not only aids in weight loss but also increases plasma levels of genistein, a metabolite linked to reduced severity of non-alcoholic fatty liver disease (NAFLD), as shown in a study involving 5 patients and rodent models.

The study found that the changes in gut microbiota after surgery play a crucial role in elevating plasma genistein levels, suggesting that bariatric surgery can have beneficial effects on liver health through mechanisms beyond just weight loss.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Increased plasma genistein after bariatric surgery could promote remission of NAFLD in patients with obesity. Wang, G., Wang, Y., Bai, J., et al.[2023]

Bariatric surgery can significantly improve or even resolve nonalcoholic fatty liver disease (NAFLD), which is a serious condition linked to metabolic syndrome.

The benefits of bariatric surgery for NAFLD are attributed not only to weight loss but also to improvements in insulin resistance and reductions in inflammatory proteins.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Effects of Metabolic Surgery on Fatty Liver Disease and Nonalcoholic Steatohepatitis. Clanton, J., Subichin, M.[2022]

In a study of 90 morbidly obese patients with a BMI between 35 and 40 kg/m2, high levels of parathyroid hormone (PTH) were significantly associated with the presence of hepatic fibrosis, steatosis, and NASH/NAFLD, indicating that PTH could be a useful biomarker for liver health in this population.

The research suggests that measuring PTH levels before and after bariatric surgery may help in assessing liver conditions, but further randomized controlled trials are needed to confirm these findings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The predictive role of parathyroid hormone for non-alcoholic fatty liver disease based on invasive and non-invasive findings in candidates of bariatric surgery. Jamialahmadi, T., Nematy, M., Jangjoo, A., et al.[2022]

In a randomized trial involving 288 participants with non-alcoholic steatohepatitis (NASH), bariatric-metabolic surgery (Roux-en-Y gastric bypass and sleeve gastrectomy) resulted in significantly higher rates of NASH resolution compared to lifestyle modifications, with 56% and 57% of participants achieving resolution respectively, versus only 16% in the lifestyle group.

The study reported no deaths or life-threatening complications, indicating that bariatric surgery is a safe option for treating NASH, although 6% of participants experienced severe adverse events that were manageable without re-operations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bariatric-metabolic surgery versus lifestyle intervention plus best medical care in non-alcoholic steatohepatitis (BRAVES): a multicentre, open-label, randomised trial. Verrastro, O., Panunzi, S., Castagneto-Gissey, L., et al.[2023]

Bariatric surgery in 196 patients with advanced NASH led to significant histological improvements, with 29% achieving normal liver histology and 74% experiencing NASH resolution without fibrosis progression after an average follow-up of 6 years.

Despite these improvements, advanced fibrosis persisted in 47% of patients, indicating that while weight loss and metabolic improvements are beneficial, they may not be enough to fully reverse advanced fibrosis, especially in older patients or those undergoing sleeve gastrectomy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Persistence of severe liver fibrosis despite substantial weight loss with bariatric surgery. Pais, R., Aron-Wisnewsky, J., Bedossa, P., et al.[2022]

Bariatric surgery may be an effective treatment option for nonalcoholic fatty liver disease, particularly in patients with liver fibrosis and compensated cirrhosis, as suggested by a review of existing outcomes.

Despite the promising potential of bariatric surgery for improving liver health, more research is needed to fully understand its effects on liver fibrosis and cirrhosis in patients with nonalcoholic fatty liver disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Effect of Bariatric Surgery on the Spectrum of Fatty Liver Disease. Nostedt, JJ., Switzer, NJ., Gill, RS., et al.[2018]

Bariatric surgery significantly reduces various histological features of non-alcoholic fatty liver disease (NAFLD) in obese patients, including steatosis, fibrosis, hepatocyte ballooning, and lobular inflammation, indicating a strong therapeutic effect on liver health.

Post-surgery, patients also experience significant reductions in liver enzyme levels (ALT, AST, ALP, and gamma-GT), which are important markers of liver injury, further supporting the efficacy of bariatric surgery in improving NAFLD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bariatric Surgery and Non-Alcoholic Fatty Liver Disease: a Systematic Review of Liver Biochemistry and Histology. Bower, G., Toma, T., Harling, L., et al.[2022]

Patients with nonalcoholic fatty liver disease (NAFLD) who underwent bariatric surgery (BS) experienced 35% lower inpatient mortality and shorter hospital stays compared to those without NAFLD, indicating that BS is safe and effective for this group.

Bariatric surgery not only reduces mortality and complications for NAFLD patients but also has the potential to improve liver health by significantly reducing liver inflammation and fibrosis through substantial weight loss.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nonalcoholic fatty liver disease does not predict worse perioperative outcomes in bariatric surgery. Mavilia, MG., Wakefield, D., Karagozian, R.[2020]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9865319/

GLP-1 Receptor Agonists in Non-Alcoholic Fatty Liver Disease GLP-1 receptor agonists (GLP-1 RAs) have shown a significant impact on body weight and clinical, biochemical and histological markers of fatty liver and ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4064081/

Incretin based therapies: A novel treatment approach for non ... They suggest that GLP-1 analogues might have beneficial effect on hepatic steatosis acting as insulin sensitizers and directly by stimulating GLP-1 receptors ...

3. sciencedirect.com sciencedirect.com/science/article/pii/S0168822724005850

Incretin-based investigational therapies for the treatment of ... In both studies, liver fat reduced significantly after 6 months of treatment with liraglutide 3.0 mg or structured lifestyle intervention; liver fat reduction ...

4. nature.com nature.com/articles/s41598-025-89408-z

Glucagon-like peptide-1 receptor agonists improve ... The results revealed that patients initiating GLP-1 agonist therapy experienced significantly lower rates of hepatic decompensation events ...

5. journal-of-hepatology.eu journal-of-hepatology.eu/article/S0168-8278(23)05046-8/fulltext

Incretins (GLP-1 receptor agonists and dual/triple ... These effects in response to GLP-1 agonist therapy are associated with an improvement in glucose control in patients with MASH and impaired glucose tolerance ...

6. academic.oup.com academic.oup.com/jcag/article/8/2/47/7989366

Effects of GLP-1 receptor agonist therapy on resolution of ... Treatment with GLP-1RA in NAFLD patients for ≥6 months can probably lead to improvement in NASH on liver biopsy and reduce liver steatosis on imaging.