From the Guidelines
Ezetimibe is generally not considered hepatotoxic, with a favorable safety profile regarding liver function, as evidenced by the 2022 ACC expert consensus decision pathway 1. This cholesterol-lowering medication works by reducing intestinal cholesterol absorption and has a minimal risk of liver damage compared to other lipid-lowering medications like statins. While rare cases of mild, transient elevations in liver enzymes have been reported, clinically significant liver injury from ezetimibe monotherapy is extremely uncommon. Some key points to consider include:
- The medication's mechanism of action primarily in the small intestine rather than the liver likely contributes to its favorable hepatic safety profile.
- When ezetimibe is used alone, the risk of liver damage is minimal.
- However, when combined with statins, there may be a slightly increased risk of liver enzyme elevations, though still relatively low.
- Patients with pre-existing liver disease should be monitored more closely when taking ezetimibe, with periodic liver function tests recommended during treatment, as noted in the 2019 systematic review for the 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol 1.
- The IMPROVE-IT trial found that ezetimibe was well tolerated, with no statistically significant differences in adverse effects for myopathy, rhabdomyolysis, liver function test abnormalities, or cancer 1. Overall, most patients can take ezetimibe without concern for liver toxicity, making it a useful option for those who cannot tolerate statins due to liver-related side effects.
From the FDA Drug Label
Ezetimibe tablets may cause serious side effects including: increased liver enzymes. An increase in liver enzymes can happen in people taking ezetimibe tablets alone or with statins. Inform patients that ezetimibe tablet may cause liver enzyme elevations [see Warnings and Precautions (5. 2)]. 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%). Hepatobiliary Disorders: elevations in liver transaminases, including elevations more than 5 X ULN; hepatitis; cholelithiasis; cholecystitis
Ezetimibe may be hepatotoxic. The FDA drug label reports that ezetimibe can cause increased liver enzymes and elevations in liver transaminases, including elevations more than 5 X ULN, hepatitis, cholelithiasis, and cholecystitis 2, 2. Patients should be advised to report any symptoms of liver enzyme elevations, such as unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever 2.
From the Research
Ezetimibe Hepatotoxicity
- Ezetimibe has been evaluated for its safety and effectiveness in liver transplant recipients with hypercholesterolemia, and it was found to be effective with few side effects and no interaction with immunosuppressive regimens 3.
- However, there have been reports of severe hepatic side effects of ezetimibe, including hepatotoxicity, severe cholestatic hepatitis, or acute autoimmune hepatitis 4.
- Hepatic impairment has been shown to significantly increase the systemic exposure of ezetimibe and its active metabolites, which may be related to changes in enzyme and transporter activities 5.
- The mechanisms by which ezetimibe affects lipoprotein metabolism are not completely understood, but it is thought to modulate the expression of key genes involved in intestinal lipoprotein metabolism 6.
- Ezetimibe has been compared to other lipid-lowering therapies, including statins and bile acid sequestrants, in terms of efficacy and safety, and it has been found to be a useful addition to statin therapy for lowering low-density lipoprotein cholesterol levels 7.