Greek Study Offers Reassurance About Statin Usage in Patients with Abnormal Liver Tests

Among the 1600 patients randomized in the GREACE (Greek Atorvastatin and Coronary Heart Disease Evaluation) study, 437 had moderately abnormal liver tests at baseline suggesting non-alcoholic fatty liver disease (NAFLD).

In a post-hoc analysis of this subset of patients published in the Lancet, the GREACE Study Collaborative Group reported a dramatic 68% reduction in the rate of cardiovascular events in patients in the statin group. Cardiovascular events occurred in 30% of patients in the non-statin group (63 out of 210) compared to 10% of patients in the statin group (22 of 227). The authors say their results mean that “statin treatment is safe and can improve liver tests and reduce cardiovascular morbidity in patients with mild-to-moderately abnormal liver tests that are potentially attributable to non-alcoholic fatty liver disease.” In addition, the authors note that statin treatment was associated with improvement in liver tests.

Finally, the authors acknowledge that the benefits of statins in these patients “might be attributable to the presence of NAFLD, since alcohol misuse and other liver diseases were excluded.”

In an accompanying comment, Ted Bader estimates that 10-30% of patients who need statins might be denied statin treatment because of liver functions tests. “Statin-induced hepatotoxicity is a myth,” he writes. He recommends that statin manufacturers should request FDA approval to remove language about liver toxicity from drug labels. “For too long,” he writes, “a raised ALT after starting a statin has been erroneously thought to represent liver disease. For too long, patients with liver disease have been denied statins for their hypercholesterolemia.”

Here is the Lancet press release:

STATINS IMPROVE LIVER FUNCTION AND SUBSTANTIALLY REDUCE CARDIOVASCULAR EVENTS IN PATIENTS WITH ABNORMAL LIVER TESTS

Contrary to widespread belief, patients with abnormal liver function who are given long-term statin treatment do not face an increased risk of liver disease, according to an Article published Online First in The Lancet. In fact, statins can improve liver function in patients with abnormal liver tests. Moreover, this study is the first to show a substantially greater cardiovascular benefit in patients with abnormal liver function tests compared with patients who have normal liver tests. These findings suggest that statins are a safe and promising treatment strategy for patients with non-alcoholic fatty liver disease (NAFLD).

Statins inhibit the liver’s production of cholesterol and long-term treatment reduces the risk of cardiovascular events such as heart attacks and strokes. A rare adverse effect of statin use is increased levels of liver enzymes or serum transaminases like alanine aminotransferase (ALT). As a result, many physicians are reluctant to prescribe statins to patients with elevated ALT.

Most patients with high ALT will have NAFLD which affects up to a third of American, European and Japanese adults. The disease is common in patients with high cholesterol who have a substantially increased risk of cardiovascular disease and who would benefit from treatment with statins. However, the safety and efficacy of long-term statin treatment in these patients is unclear. Previous small and short-term studies in patients with raised ALT because of NAFLD have suggested that they are safe and improve liver tests and liver histology.

To provide more evidence, a team led by Vasilis Athyros from the Hippokration University Hospital in Thessaloniki, Greece and Dimitri Mikhailidis from University College London, London, UK, conducted a post hoc analysis of the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) study*to assess whether long-term (3 year) statin treatment (mainly atorvastatin) is safe and effective in patients thought to have NAFLD. Of 437 patients with moderately abnormal liver tests (defined as less than three times the upper limit of normal before beginning treatment), 227 were treated with a statin and 210 were not treated.

Overall, liver-related adverse effects occurred no more often in the group who were given statins. Over 3 years follow-up, ALT improved or normalised in patients who were given statins, but in the group not taking statins liver tests worsened.

Importantly, patients who started the trial with abnormal liver function tests gained the greatest cardiovascular benefit of all—showing a 39% lower risk of having a cardiovascular event than patients in the GREACE study who had treated with a statin who had normal liver tests, and a 68% reduction in the relative risk of cardiovascular events compared with patientsfrom GREACE who did not receive a statin.

The authors conclude: “The risk-to-benefit ratio of long-term statin treatment favours statin administration even for patients with moderately abnormal liver tests.”

In an accompanying Comment, Ted Bader from the University of Oklahoma Health Sciences Center, Oklahoma City, USA, says that: “For too long, a raised ALT after starting a statin has been erroneously thought to represent liver disease. For too long, patients with liver disease have been denied statins for their hypercholesterolaemia.”

He points out that: “Despite the absence of liver injury from statins, a US survey showed that 50% of academic physicians would be reluctant to give a statin to a patient with an ALT of more than 1.5 times the upper limit of normal…10–30% of patients who need statins…would therefore be denied a statin.”

He concludes: “Most physicians believe that statins cause liver disease because of the language of package inserts. Drug companies should be encouraged to request the deletion of this point from the insert.”