Semaglutide’s Role in the Treatment of Liver Disease - A Review

Introduction

Liver diseases have been on the rise in recent years. It is considered to be a major health issue in the world. The common liver disease is non-alcoholic fatty liver disease (NAFLD). This condition may turn into a more serious form called nonalcoholic steatohepatitis (NASH).

The reason for the rise of these liver diseases is mainly the rise of obesity and type 2 diabetes among people. In recent years, it was found that glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are found to provide metabolic benefits other than glycemic control. Among these, Semaglutide has been found to have promising effects on liver-related outcomes.

How Does Semaglutide Affect the Liver?

Semaglutide is a GLP-1 RA. It is mainly used for weight loss and type 2 diabetes. Along with lifestyle modifications such as dietary restrictions and exercise, this drug may help achieve weight loss. It has shown positive effects when given to those with liver diseases.

Liver diseases called NAFLD and NASH were changed to metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic-associated steatohepatitis (MASH) in the year 2023 by a few scientists, doctors, and patients.

MASLD is a condition that occurs due to a buildup of fat in the liver. The risk factors for the development of MASLD. Include:

1. Obesity.

2. Type 2 diabetes.

3. High blood pressure.

MASLD does not show any noticeable symptoms, but it can progress to a more severe form called MASH. MASH involves inflammation and damage to the liver. A study noted that around 30 percent of the world's population is affected by MASLD.

Over time, the MASH may lead to the following:

1. Liver fibrosis.

2. Liver cirrhosis.

3. Liver failure.

The Food and Drug Administration (FDA) has not yet approved semaglutide for treating liver diseases, but research has found that it can help reduce fat in the liver. This may be because it aids in weight loss.

Mechanism of Action in Treating Liver Disease:

Reduction of Hepatic Steatosis (Fat Accumulation in the Liver): As Semaglutide can reduce weight and help improve type 2 diabetes, it can indirectly help reduce liver fat. Semaglutide can act on hypothalamus. This action helps reduce appetite and calorie intake, which further helps reduce weight gain. Weight loss, hence, reduces liver fat, inflammation, and insulin resistance.

Insulin Sensitization: Semaglutide, like a GLP-1 RA, helps stimulate insulin secretion in a glucose-dependent manner. It reduces glucagon secretion. This, in turn, reduces hepatic glucose production. This action improves overall insulin sensitivity. Hence, it reduces insulin resistance, which is an important factor in MASLD. Reduced hepatic glucose levels help improve glucose metabolism. This also decreases fat in the liver.

Antiinflammatory Action: Semaglutide exhibits antiinflammatory actions by decreasing the levels of pro-inflammatory cytokines like tumor necrosis factor (TNF)-alpha and interleukin (IL)-6, and it may directly show its effects on hepatic immune cells called Kupffer’s cells.

Modulating Fibrosis: Researchers have noticed that Semaglutide can slow the progression or reduce liver fibrosis. This is possible because it reduces inflammation and fat accumulation, as well as its weight loss action and improvement in metabolic actions.

GLP-1 Receptors in the Liver: The liver contains a few GLP-1 receptors. Hence, Semaglutide's actions are indirect. It modulates the levels of insulin or glucagon, weight loss, and inflammation.

What Is the Clinical Evidence Supporting Semaglutide in NAFLD and NASH?

Researchers have been trying to determine whether Semaglutide helps in conditions like NAFLD and NASH. Some of them include:

Phase 2 Trial: Semaglutide in NASH.

In this study, Semaglutide was given along with a placebo to determine its effect on NASH and liver fibrosis. It was found that Semaglutide can help resolve NASH without affecting fibrosis. There was a significant reduction in ALT (Alanine Transaminase), AST (Aspartate Aminotransferase), and liver fat. There was also an improvement in liver fibrosis, but this result was not significant.

NAFLD Imaging Studies (Magnetic Resonance Imaging (MRI)-PDFF (Proton Density Fat Fraction) Studies):

Many studies using MRI-PDFF exhibit a 30 to 50 % reduction in liver fat content after using Semaglutide. This improvement can be correlated with weight loss and insulin sensitivity. A study done in 2020 showed that Semaglutide can improve hepatic steatosis and liver fibrosis. It was also noted that there was a drop in the levels of ALT.

Other Studies and Meta-Analyses: Other systematic reviews and meta-analyses have shown that Semaglutide can significantly improve hepatic steatosis and levels of transaminases. They also noted that, though there is no significant improvement in liver fibrosis, it was noted that there is no worsening of liver fibrosis.

A study done by the director of Virginia Commonwealth University’s Liver Institute suggests that Semaglutide can halt or reverse liver disease.

ESSENCE (Effect of Semaglutide in Subjects with Non-cirrhotic Non-alcoholic Steatohepatitis) Phase 3 Trial: In this trial, participants were given either Semaglutide or a placebo. Participants were patients with biopsy-proven MASH and stage 2 or 3 fibrosis. This clinical trial is being done to evaluate the effect of Semaglutide in treating a specific type of fatty liver disease.

What Are the Impacts of Semaglutide on Liver Enzymes, Fibrosis, and Fatty Liver Disease?

Semaglutide showed its promising effects on liver health.

The impacts of Semaglutide on the liver include:

• It helps reduce liver enzymes like ALT, AST, and GGT (gamma-glutamyl transferase). When these enzymes are lowered, one can observe decreased inflammation and improved liver function.

• Semaglutide has not been found to significantly reduce liver fibrosis, but it can slow its progression. Since it can help reduce weight and provide glycemic control, it can indirectly reduce the progression of liver fibrosis.

• Semaglutide helps in treating fatty liver diseases.

What Is the Comparison of Semaglutide With Other Treatments for Fatty Liver Disease?

Semaglutide can provide a promising treatment for fatty liver. Its comparison can be done with other treatments. These include:

Lifestyle Modifications:

Many individuals with NAFLD usually do not develop serious problems. NAFLD is associated with obesity. Lifestyle changes to be done include:

• Exercising regularly.

• Quitting smoking.

• Eating a balanced diet (reducing the intake of sugary and processed foods).

• Reducing alcohol intake.

• Managing stress levels.

These changes can help people lose weight and treat fatty liver disease.

Semaglutide, along with weight loss, can help improve the metabolic process, whereas lifestyle changes are long-term and sustainable. These help reduce weight and treat metabolic syndrome.

Resmetirom:

Resmetirom is the first Food and Drug Administration (FDA)-approved drug for treating NAFLD. It helped to reduce liver fat. The disadvantage of this drug is that it cannot be used in those with cirrhosis.

Obticholic Acid (OCA):

This medication is considered to be the only drug used for fibrosis, but FDA approval has not yet been granted.

What Is the Safety Profile and Side Effects of Semaglutide in Liver Disease Patients?

Semaglutide can be effectively used to treat liver diseases like NAFLD and NASH. These exhibit certain side effects. These include:

Common side effects include:

• Nausea.

• Vomiting.

• Diarrhea.

• Constipation.

• Abdominal pain.

Serious or rare side effects include:

• Pancreatitis.

• Gall bladder disease.

• Hypoglycemia (low blood sugar).

• Renal impairment.

What Are the Future Researches Going on About Semaglutide?

Semaglutide is being researched for its effects on various diseases other than obesity and type 2 diabetes.

Liver Disease: New research has found that it can help treat liver diseases like NAFLD and NASH.

Cardiac Disease: A study has found that Semaglutide injections can reduce the risk of major adverse cardiovascular events (MACE).

Neurodegenerative Disease: Semaglutide is being studied for its effect on Alzheimer’s disease.

Respiratory Conditions: Studies are being conducted to determine Semaglutide’s effect on asthma, especially obesity-related asthma.

Brain Health: Studies are being done to determine whether Semaglutide helps in preventing cognitive decline.

Obesity Management Enhancement: These studies are being conducted to determine whether higher doses of Semaglutide can bring more weight loss.

Conclusion:

Semaglutide is mainly used for treating obesity and type 2 diabetes. It was found to play a role in liver diseases as well. It was known to reduce liver enzymes and help resolve NASH. It was found to be safe, though it has some common side effects. It was observed that it does not cause any hepatotoxicity. Future research is being conducted to determine its role in treating various other diseases as well. Hence, it is important to know about Semaglutide and its role.

Key Takeaway From iCliniq

Semaglutide is a drug that is trending as it has a role in treating liver diseases, along with obesity and type 2 diabetes. It is being researched for its role in various other diseases like heart health, brain health, etc. To know more about and treat liver diseases, you can consult our doctors at iCliniq.