Should Zetia (ezetimibe) be held in patients with transaminitis?

Ezetimibe Should Be Held in Patients with Transaminitis Greater Than 3 Times Upper Limit of Normal

Ezetimibe should be discontinued if transaminases are confirmed to be greater than 3 times the upper limit of normal (ULN). 1

Safety Profile of Ezetimibe and Liver Function

• The American College of Cardiology/American Heart Association guidelines recommend monitoring transaminase levels when ezetimibe is coadministered with a statin and discontinuing ezetimibe if persistent ALT elevations greater than 3 times ULN occur 1
• The FDA drug label notes that post-marketing reports include cases of elevated liver transaminases, including elevations more than 5 times ULN, though causality is difficult to establish due to voluntary reporting 2
• While ezetimibe metabolism is not primarily dependent on hepatic cytochrome P450 enzymes and is primarily eliminated via glucuronidation and fecal excretion, it can still cause hepatotoxicity in rare cases 3

Management Algorithm for Ezetimibe in Patients with Transaminitis

Severity-Based Approach:

• Mild transaminitis (< 3× ULN):

  • Continue ezetimibe with close monitoring of liver function tests every 2-4 weeks 1
  • Consider more frequent monitoring if transaminases continue to rise 2

• Moderate transaminitis (3-5× ULN):

  • Discontinue ezetimibe if elevations are persistent 1
  • Consider alternative lipid-lowering strategies 1

• Severe transaminitis (> 5× ULN):

  • Immediately discontinue ezetimibe 1
  • Evaluate for other causes of liver injury 2
  • Monitor until resolution 2

Evidence for Ezetimibe-Related Hepatotoxicity

• Case reports have documented severe hepatocellular drug-induced liver disease after ezetimibe therapy, with patients recovering after drug withdrawal 4
• Severe cholestatic hepatitis and acute autoimmune hepatitis have been reported as rare but serious hepatic side effects of ezetimibe 5
• When used in combination with statins, the incidence of consecutive increased transaminases (≥3× ULN) was higher (1.3%) compared to patients treated with statins alone (0.4%) 2

Special Considerations

• Ezetimibe is not recommended for use in patients with moderate to severe hepatic impairment 6
• If a patient has pre-existing liver disease, the risk-benefit ratio should be carefully evaluated before initiating ezetimibe 7
• For patients requiring lipid-lowering therapy who develop transaminitis on ezetimibe, consider alternative agents such as bile acid sequestrants, which have different metabolic pathways 1

Monitoring Recommendations

• Obtain baseline hepatic transaminases before initiation of ezetimibe 1
• When ezetimibe is used as monotherapy in patients with normal baseline liver function, routine monitoring of transaminases is not mandated but should be performed if clinically indicated 7
• When coadministered with a statin, monitor transaminase levels as clinically indicated 1
• If abnormal liver tests develop during treatment, promptly evaluate for causality and consider drug discontinuation 2

Conclusion

The evidence clearly supports holding ezetimibe in patients with significant transaminitis, particularly when levels exceed 3 times the upper limit of normal. While ezetimibe is generally well-tolerated, its potential to cause or exacerbate liver injury warrants caution in patients with pre-existing liver disease or elevated transaminases.