Can semaglutide (glucagon-like peptide-1 receptor agonist) be given to a patient with compensated cirrhosis?

From the Guidelines

Semaglutide can be used in patients with compensated cirrhosis, but caution is advised, as stated in the 2024 guidelines 1. For patients with Child-Pugh Class A (compensated) cirrhosis, no dose adjustment is typically required. However, clinical experience in this population is limited, so careful monitoring is recommended. Semaglutide is primarily metabolized through proteolytic cleavage of the peptide backbone and beta-oxidation of the fatty acid side chain, rather than through hepatic metabolism, which makes it relatively safe in liver disease. The medication is cleared through multiple organ systems, not just the liver. Some key points to consider when using semaglutide in patients with compensated cirrhosis include:

• Monitoring for potential side effects such as nausea, vomiting, and hypoglycemia (if used with insulin or sulfonylureas), as these may be less tolerated in liver disease.
• Starting with the lowest available dose and titrating slowly based on tolerance.
• Using Ozempic (injectable semaglutide) with a starting dose of 0.25 mg once weekly for 4 weeks, then increasing to 0.5 mg weekly if tolerated.
• Avoiding semaglutide in decompensated cirrhosis (Child-Pugh B or C) due to insufficient safety data in this population, as noted in the 2021 study 1 and the 2024 guidelines 1. It's also important to consider the patient's overall health and the presence of any other comorbidities, as well as the potential benefits and risks of using semaglutide in this population, as discussed in the 2023 and 2024 guidelines 1.

From the FDA Drug Label

Patients with Hepatic impairment - Hepatic impairment does not have any impact on the exposure of semaglutide The pharmacokinetics of semaglutide were evaluated in patients with different degrees of hepatic impairment (mild, moderate, severe) compared with subjects with normal hepatic function in a study with a single-dose of 0. 5 mg semaglutide. No dose adjustment of OZEMPIC is recommended for patients with hepatic impairment. In a study in subjects with different degrees of hepatic impairment, no clinically relevant change in semaglutide pharmacokinetics (PK) was observed [see Clinical Pharmacology (12. 3)].

Semaglutide can be given to a patient with compensated cirrhosis. The drug label states that hepatic impairment does not have any impact on the exposure of semaglutide, and no dose adjustment is recommended for patients with hepatic impairment, including those with compensated cirrhosis 2.

From the Research

Semaglutide Use in Compensated Cirrhosis

• Semaglutide, a glucagon-like peptide-1 receptor agonist, has been studied in patients with compensated cirrhosis, with mixed results 3, 4, 5, 6, 7.
• A case report described liver decompensation in a patient with non-alcoholic steatohepatitis (NASH)-associated cirrhosis treated with semaglutide, highlighting the need for caution in this population 3.
• A randomized, placebo-controlled phase 2 trial found no significant difference in liver fibrosis improvement or NASH resolution between semaglutide and placebo in patients with NASH-related cirrhosis, although no new safety concerns were raised 4.
• A population-based cohort study suggested that glucagon-like peptide-1 receptor agonist use, including semaglutide, may be associated with lower risks of mortality, cardiovascular events, decompensated cirrhosis, hepatic encephalopathy, and liver failure in patients with type 2 diabetes and compensated liver cirrhosis 5.
• A phase 3 trial of semaglutide in metabolic dysfunction-associated steatohepatitis (MASH) found improved liver histologic results, including resolution of steatohepatitis and reduction in liver fibrosis, although gastrointestinal adverse events were more common in the semaglutide group 6.
• An observational study using Swedish healthcare registers suggested that glucagon-like peptide-1 receptor agonists, including semaglutide, may be associated with a lower risk of major adverse liver outcomes in patients with chronic liver disease and type 2 diabetes, particularly in those who adhere to therapy over time 7.

Key Considerations

• The use of semaglutide in patients with compensated cirrhosis requires careful consideration of the potential benefits and risks, including the risk of liver decompensation 3.
• Patients with NASH-related cirrhosis may not experience significant improvements in liver fibrosis or NASH resolution with semaglutide, although the drug may be safe in this population 4.
• Glucagon-like peptide-1 receptor agonists, including semaglutide, may be beneficial in patients with type 2 diabetes and compensated liver cirrhosis, reducing the risk of adverse outcomes 5.
• Semaglutide may be effective in improving liver histologic results in patients with MASH, although gastrointestinal adverse events are common 6.
• Further research is needed to confirm the potential benefits and risks of semaglutide in patients with compensated cirrhosis and to determine the optimal use of this medication in this population 3, 4, 5, 6, 7.