From the Guidelines
Zetia (ezetimibe) can elevate liver enzymes, although this is a relatively rare side effect. According to the 2022 ACC expert consensus decision pathway on the role of nonstatin therapies for LDL-cholesterol lowering in the management of atherosclerotic cardiovascular disease risk 1, ezetimibe may cause persistent elevations in hepatic transaminases, particularly when used in combination with statin therapy. The study notes that monitoring of hepatic transaminases is recommended before and during treatment with ezetimibe, based on the monitoring recommendations for statin therapy.
Key Points to Consider
- Ezetimibe is not recommended in patients with moderate to severe hepatic impairment 1.
- The medication works by inhibiting the NPC1L1 protein, reducing cholesterol absorption in the small intestine, which is a different mechanism of action compared to statins that act directly on the liver.
- While the risk of liver enzyme elevation is present, it is generally considered to be lower with ezetimibe compared to some other lipid-lowering therapies.
- Patients should be aware of symptoms that could indicate liver problems, such as unusual fatigue, abdominal pain, dark urine, or yellowing of the skin or eyes, and should contact their healthcare provider promptly if these symptoms occur.
Clinical Implications
The potential for ezetimibe to elevate liver enzymes underscores the importance of regular monitoring of liver function tests in patients taking this medication, especially when it is used in combination with statins. Healthcare providers should weigh the benefits of ezetimibe in lowering LDL-cholesterol and reducing the risk of major adverse cardiovascular events against the potential risks, including the rare but possible elevation of liver enzymes. As noted in the study, ezetimibe is generally well-tolerated, and the availability of generic formulations can make it a more accessible option for patients requiring nonstatin therapies for LDL-cholesterol management 1.
From the FDA Drug Label
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. Inform patients that ezetimibe tablet may cause liver enzyme elevations [see Warnings and Precautions (5. 2)].
Yes, Zetia (ezetimibe) may elevate liver enzymes. Patients should be monitored for liver enzyme abnormalities, and the medication should be withdrawn if significant elevations persist 2.
From the Research
Zetia and Liver Enzymes
- Zetia (ezetimibe) is a cholesterol-lowering agent that has been reported to cause hepatic toxicity in some cases, particularly when used in conjunction with statin medications 3, 4.
- Studies have shown that ezetimibe can cause elevations in liver enzymes, although this is relatively rare 3, 4.
- In one case report, a patient developed severe isolated hyperbilirubinemia after starting ezetimibe therapy, which resolved when the drug was stopped 3.
- Another study reported a case of serious hepatocellular drug-induced liver disease after 4 months of therapy with ezetimibe, which also resolved after withdrawal of the drug 4.
- However, a study of liver transplant recipients with hypercholesterolemia found that ezetimibe was effective in reducing LDL levels with few side effects, including a transient elevation in liver enzymes in one subject 5.
Mechanism of Action
- Ezetimibe works by inhibiting the intestinal absorption of dietary and biliary cholesterol, which can lead to a reduction in plasma cholesterol levels 6, 7.
- The drug undergoes glucuronidation to a single metabolite and localizes at the intestinal wall, where it binds to Niemann-Pick C1 Like 1 (NPC1L1) to prevent cholesterol absorption 6.
- Ezetimibe has a favorable drug-drug interaction profile, with no significant effects on plasma levels of statins or other commonly used medications 7.