2008 Medical Journal Articles Describe Two Cases; Authors Suggest Liver Testing At Start Of Therapy And When Titrating Dosage Is Necessary

(Posted by Tom Lamb at DrugInjuryWatch.com)

In December 2007 we told you about an article by New York Times (NYT) reporter Alex Berenson, "Data About Zetia Risks Was Not Fully Revealed", which revealed that Merck and Schering-Plough had conducted several studies of Zetia that raised the possibility that Zetia can cause liver damage when used long-term with statin drugs.  The drug companies, however, decided not to publish the results of those Zetia studies, according to this NYT article.

Now, in late summer 2008, two medical journal articles have been published which associate Zetia (ezetimibe) with liver failure and liver disease.

From the September 1, 2008 edition of Pharmacotherapy we get an article, "Simvastatin-ezetimibe-induced hepatic failure necessitating liver transplantation", that discusses a case of liver failure involving Vytorin — which is a combination of Zetia with the statin drug Zocor.  The article points out that reports liver damage reports involving Zetia or Vytorin have not been widely published to date.  It continues with one particular case report involving liver failure in a patient using Vytorin.  From the abstract from this August 2008 Pharmacotherapy article:

We describe a 70-year-old Hispanic woman who developed fulminant hepatic failure necessitating liver transplantation 10 weeks after conversion from simvastatin [or Zocor] 40 mg/day to simvastatin 10 mg-ezetimibe 40 mg/day [i.e., Vytorin]. The patient's lipid panel had been maintained with simvastatin for 18 months before the conversion without evidence of hepatotoxicity. A routine laboratory work-up 10 weeks after conversion revealed elevated serum aminotransferase levels. [The Vytorin] and escitalopram (which she was taking for depression) were discontinued, and other potential causes of hepatotoxicity were excluded. A repeat work-up revealed further elevations in aminotransferase levels, and liver biopsy revealed evidence of moderate-to-severe drug toxicity. She underwent liver transplantation with an uneventful postoperative course….  To our knowledge, this is the first case report of [Vytorin]-induced liver failure that resulted in liver transplantation.

Thereafter, the article authors — from the Division of Clinical and Administrative Pharmacy, at University of Iowa's College of Pharmacy — posit a theory on how Vytorin and Zetia can cause liver failure:

[Zetia] undergoes extensive glucuronidation by uridine diphosphate glucoronosyltransferases (UGT) in the intestine and liver and may have inhibited the glucuronidation of simvastatin hydroxy acid, resulting in increased simvastatin exposure and subsequent hepatotoxicity….  We postulate that the mechanism of the [Vytorin]-induced hepatotoxicity is the increased simvastatin exposure by ezetimibe inhibition of UGT enzymes.

These authors conclude with the suggestion that liver function tests should be carefully monitored when starting Vytorin therapy and when titrating the Vytorin dosage.

The second article, "Serious drug-induced liver disease secondary to ezetimibe", published in World Journal of Gastroenterology, August 28, 2008 edition, focuses on just Zetia.  It reports the case of a woman who developed a "serious hepatocellular drug-induced liver disease" after taking Zetia 10 mg daily for a four month period, then recovered after she was taken off the Zetia.  Based on this case, the authors concluded:

[Zetia] may produce serious toxic hepatitis and prompt withdrawal is mandatory in case of a significant abnormality in liver testing after beginning or during treatment with [Zetia].

We will continue to watch for reports of liver injury associated with Vytorin and Zetia.  If you are aware of such a case, please share your information with us.