Can Semaglutide (generic name) cause elevated liver enzymes, specifically hepatocellular injury or abnormal liver function tests?

From the Guidelines

Semaglutide can cause elevated liver enzymes in some patients, though this is generally uncommon, and most cases are mild and transient, not requiring discontinuation of the medication. The evidence from a 2021 study published in Gastroenterology 1 suggests that semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, has been tested in patients with type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD), with some studies showing improvement in liver histology and reduction in liver fat content. However, the study also notes that the dose used in the study is not currently available for prescription in patients with diabetes, and the weight loss and metabolic effects achieved were similar overall to the effects seen with currently available doses for management of diabetes.

Some key points to consider when prescribing semaglutide to patients with pre-existing liver disease include:

• Monitoring liver function tests more closely, particularly during the first few months of treatment
• Recommending regular liver function tests to assess for any potential liver enzyme elevations
• Being aware of the potential for semaglutide to cause changes in body weight or metabolic improvements, which may relate to the elevations in liver enzymes
• Informing patients to contact their healthcare provider immediately if they develop symptoms such as right upper quadrant pain, nausea, vomiting, dark urine, or jaundice while taking semaglutide

It's also important to note that the benefits of semaglutide for diabetes management or weight loss typically outweigh the risk of mild liver enzyme elevations, but individual risk assessment by a healthcare provider is important. Additionally, other studies have shown that GLP-1 receptor agonists, such as dulaglutide, can also reduce liver fat content and transaminases in people with T2D and NAFLD 1.

In terms of the mechanism behind these elevations, it's not fully understood, but may relate to changes in body weight or metabolic improvements rather than direct liver toxicity. The 2023 study published in the Journal of the American College of Radiology 2, 3 provides guidance on the management of abnormal liver function tests, including the use of hepatotoxic drugs and the interpretation of liver biochemical tests. However, these studies do not provide specific information on the use of semaglutide and its potential to cause elevated liver enzymes.

Overall, while semaglutide can cause elevated liver enzymes in some patients, the benefits of the medication for diabetes management or weight loss typically outweigh the risks, and individual risk assessment by a healthcare provider is important to minimize potential adverse effects.

From the Research

Semaglutide and Liver Enzymes

• The effect of semaglutide on liver enzymes has been studied in several trials 4, 5, 6, 7, 8.
• A study published in 2023 found that semaglutide treatment showed a reduction in serum alanine transaminase and aspartate transaminase levels in patients with non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH) 6.
• Another study published in 2019 found that semaglutide significantly reduced alanine aminotransferase (ALT) and high-sensitivity C-reactive protein (hsCRP) in subjects at risk of NAFLD 8.
• However, it is essential to note that semaglutide may cause gastrointestinal adverse effects, which could be a major concern 6.
• There is no direct evidence to suggest that semaglutide causes elevated liver enzymes, but rather it may have a beneficial effect on liver enzymes in patients with NAFLD or NASH 5, 6, 8.

Adverse Liver Outcomes

• A multi-institutional cohort study published in 2024 found that semaglutide was associated with a lower risk of major adverse liver outcomes (MALO) compared to other antidiabetic medications in patients with NAFLD and type 2 diabetes 5.
• The study also found that semaglutide was linked to a lower risk of all-cause mortality compared to other antidiabetic medications 5.
• However, a case report published in 2023 found that semaglutide may cause acute pancreatitis in some patients, which could be a concern for liver health 7.

Mechanism of Action

• Semaglutide is a glucagon-like peptide-1 receptor agonist (GLP-1 RA) that stimulates insulin secretion and promotes weight loss 4, 7.
• The mechanism of action of semaglutide on liver enzymes is not fully understood, but it may be related to its effects on weight loss and improvement in metabolic parameters 6, 8.