No Toxicity, Possible Cancer Benefit With Statins and HCC

Nick Mulcahy

May 08, 2013

In adults with hepatitis C virus (HCV) infection, statin use is associated with a significantly reduced risk for hepatocellular carcinoma (HCC), according to a large observational study from Taiwan.

"Statin use is a convenient and acceptable adjuvant strategy for preventing HCC in HCV-infected patients," conclude the authors, led by Yu-Tse Tsan, MD, from the National Taiwan University in Taipei.

The virus increases the risk of developing liver cancer 15- to 20-fold, they point out.

This is the first large population-based study to look at statin use and the risk for HCC, Dr. Tsan and colleagues note. Their results, from more than 260,000 HCV-infected patients, were published in April 20 in the Journal of Clinical Oncology.

Results from previous observational studies and randomized controlled trials of statins have been mixed on their protective effect for HCC, they say.

This is the first study to document a dose–response relation between statin use and the risk for HCC in HCV-infected patients. The authors found that, over a 12-month period, the greater the daily statin use, the greater the reduction in cancer risk.

When statin use was compared with no use, for an annual cumulative defined daily dose (cDDD) of 28 to 89, the adjusted hazard ratio was 0.66; for a cDDD of 90 to 180, it was 0.47; and for a cDDD above 180, it was 0.33.

The risks were calculated after controlling for a variety of confounders (age, sex, income, urbanization, liver cirrhosis, and diabetes) in 35,023 statin users and 225,841 nonusers.

In an accompanying editorial, Abby Siegel, MD, from the Columbia University Medical Center in New York City, praises the results as "compelling evidence" for an association between statin use and a significantly lower risk for HCC.

 
It is too soon to recommend off-label use of statins for HCC prevention.
 

But she does not agree that statins are ready for this clinical use. "It is too soon to recommend off-label use of statins for HCC prevention," she writes.

"We need better insight into where in the spectrum of liver disease statins might work best and the appropriate duration of treatment," Dr. Siegel adds.

Liver Toxicity

The biggest contribution of this study might be the evidence that statins are not toxic in HCV-infected patients, Dr. Siegel notes.

"There was no increase in hepatotoxicity seen with use of statins in patients with underlying HCV, which has been a concern about using these agents in patients with liver disease," she writes. In fact, the adjusted hazard ratios for myotoxicity and drug-induced liver injury were nonsignificant (1.08 and 1.30, respectively) for patients with 90 days of regular statin use.

 
We can feel more confident that statins do not cause harm in patients with liver disease.
 

With these results, "we can feel more confident that statins do not cause harm in patients with liver disease," she says.

Dr. Siegel is impressed with 2 other aspects of this study. "The results were statin specific, and were not seen with other lipid-lowering agents," she writes. In addition, the follow-up in this observational study was "relatively long, at just over 10 years." This is important because no association has been found between statin use and reduced risk for HCC in HCV-infected patients in randomized controlled trials, she notes. The implication of her comments is that, although randomized controlled trials are the gold standard for clinical evidence, they are not usually very long and therefore could miss a treatment effect.

Dr. Siegel begins her criticism of the study in a predictable place — saying that observational studies are "susceptible to bias."

Most notably, she says, because the differences between the user and nonuser groups are seen so quickly (after a cDDD of just 28 to 89), "one might suspect that other nonbiologic factors are playing a role."

Clinical trials of statins in this setting are needed, Dr. Siegel concludes. But they would be expensive to conduct because of the large numbers of patients that would be required. As a possible solution, she proposes the use of surrogate markers to better determine just where in the continuum of liver disease (leading to liver cancer) statins have an effect.

The study authors and Dr. Siegel have disclosed no relevant financial relationships.

J Clin Oncol. 2013;31:1514-1521 and 1499-1501. Abstract, Editorial

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