What are the considerations for prescribing Zetia (ezetimibe) in patients with abnormal liver function tests?

From the Guidelines

Ezetimibe (Zetia) should be used with caution in patients with abnormal liver function tests, and is generally not recommended for those with moderate to severe hepatic impairment. Before prescribing, baseline liver function tests should be obtained, and the medication should be avoided in patients with active liver disease or unexplained persistent elevations in transaminases. For patients with mild hepatic impairment, no dosage adjustment is necessary, but more frequent monitoring of liver enzymes is recommended. The standard dose remains 10 mg once daily. If a patient develops significant liver enzyme elevations (greater than 3 times the upper limit of normal) while on ezetimibe, the medication should be discontinued. This caution is warranted because ezetimibe works by inhibiting cholesterol absorption in the small intestine and is metabolized primarily in the liver. While ezetimibe itself has a relatively low risk of hepatotoxicity compared to statins, the combination of ezetimibe with statins may increase the risk of liver enzyme elevations. Regular monitoring of liver function tests is therefore important, particularly during the first year of treatment, as supported by the 2025 ACC/AHA/ACEP/NAEMSP/SCAI guideline for the management of patients with acute coronary syndromes 1. Additionally, the 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol also emphasizes the importance of careful consideration when using ezetimibe in patients with abnormal liver function tests 1. It is also worth noting that the 2014 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults provides recommendations for the safety of cholesterol-absorption inhibitors, including ezetimibe, and suggests that it is reasonable to obtain baseline hepatic transaminases before initiation of ezetimibe 1. Overall, the use of ezetimibe in patients with abnormal liver function tests requires careful consideration and monitoring to minimize the risk of adverse effects.

From the FDA Drug Label

Liver Enzyme Abnormalities and Monitoring: Increases in serum transaminases have been reported with use of ezetimibe tablets. Perform liver enzyme testing as clinically indicated and consider withdrawal of ezetimibe tablets if increases in ALT or AST ≥3 X ULN persist. Increases in serum transaminases have been reported with use of ezetimibe tablets [see Adverse Reactions (6.1)]. In controlled clinical combination studies of ezetimibe tablets initiated concurrently with a statin, the incidence of consecutive elevations (≥3 X ULN) in hepatic transaminase levels was 1.3% for patients treated with ezetimibe tablets administered with statins and 0. 4% for patients treated with statins alone.

When prescribing Zetia (ezetimibe) to patients with abnormal liver function tests, it is essential to consider the following key points:

• Liver enzyme monitoring: Perform liver enzyme testing as clinically indicated.
• Withdrawal of ezetimibe: Consider withdrawal of ezetimibe tablets if increases in ALT or AST ≥3 X ULN persist.
• Concomitant use with statins: The incidence of consecutive increased transaminases (≥3 X ULN) was higher in patients receiving ezetimibe tablets administered with statins (1.3%) than in patients treated with statins alone (0.4%) 2 2.

From the Research

Considerations for Prescribing Zetia in Patients with Abnormal Liver Function Tests

• The prescribing of medicines to patients with abnormal liver function tests (LFTs) requires careful consideration, including the use of potentially hepatotoxic drugs and dose modification in patients with cirrhosis 3.
• In patients with abnormal LFTs, it is essential to establish the cause of the abnormal liver function and determine if the patient has cirrhosis, as this will have broad-reaching implications for prescribing 3.
• Ezetimibe, the active ingredient in Zetia, has been shown to be effective in treating hypercholesterolemia in liver transplant recipients with few side effects and no interaction with immunosuppressive regimens 4.
• A study found that ezetimibe lowered LDL-C levels by 18% in liver transplant recipients, with 32% of patients achieving the target LDL level of <100 mg/dL after 6 months of treatment 4.
• Another study found that ezetimibe was well tolerated in patients with statin intolerance and was associated with a 26% fall in LDL-C, with no marked abnormalities in liver function tests or creatine kinase activity 5.

Mechanism of Action and Pharmacokinetics of Ezetimibe

• Ezetimibe acts by inhibiting the absorption of dietary and biliary cholesterol and plant sterols, resulting in intracellular cholesterol depletion 6.
• The molecular target of ezetimibe is the Niemann-Pick C1-like transporter, which is located at the brush border of the small intestine 6.
• Ezetimibe has been shown to have a favorable safety and tolerability profile, with once-daily dosing making it an attractive adjunct therapy for the treatment of hypercholesterolemia 6.

Clinical Trials and Efficacy of Ezetimibe

• Clinical studies have demonstrated beneficial improvements in the lipid profile with ezetimibe as monotherapy, with dramatic effects seen when ezetimibe is combined with other lipid-lowering drugs, particularly statins 6.
• A retrospective case-note audit found that ezetimibe lowered LDL-C levels by 20-29% across three patient groups, with a significant trend for a fall in serum creatinine levels in patients with elevated baseline creatinine values 5.
• Ezetimibe has been shown to favorably alter the LDL-C/HDL-C ratio and lower triglyceride levels, with a consistent trend for a fall in fasting triglyceride levels in patients with elevated baseline triglyceride levels 5.