Statins Reduce CV Events in People With Abnormal Liver Function Tests CME/CE

News Author: Michael O’Riordan
CME Author: Laurie Barclay, MD

December 1, 2010 — A post hoc analysis of the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) study suggests that physicians should not let mildly to moderately abnormal liver test results stop them from using a statin in patients with coronary heart disease [1]. Statin therapy is not only safe in these patients, report investigators, but it significantly reduces the risk of cardiovascular events and improves liver-function tests.

"The data in the last few years have shown that these patients with elevated liver-function tests are at a greater risk of vascular events, and we wanted to see if that were true," senior investigator Dr Dimitri Mikhailidis (University College London Medical School, UK) told heartwire . "Indeed, there was an increased risk among these patients, and we found that they also had a bigger benefit and that they improved their liver function with a statin. Also, we found the opposite in patients not treated with a statin, that their liver-function tests tended to become more abnormal over time, although this probably reflects them getting fatter over three years in the study."

In an editorial accompanying the study [2], Dr Ted Bader (University of Oklahoma Health Sciences Center, Oklahoma City) called the analysis "groundbreaking." He said it is unknown how many patients are denied statins because of preexisting changes in liver-function tests or how many have the lipid-lowering drugs stopped after elevations in liver-enzyme concentrations, but he suspects that 10% to 30% of patients who need statins might fall into this category.

"This large group represents a substantial source of cardiovascular disease, which is not being prevented," writes Bader. "Further harm ensues from the cost of monitoring with liver-function tests. One estimate conservatively placed the cost of monitoring statins with liver-function tests at US $10 billion per year."

The results of the study and editorial are published online November 24, 2010 in the Lancet.

The GREACE Trial

To heartwire , Mikhailidis said that nonalcoholic fatty liver disease (NAFLD) is the most common cause of abnormal liver-function tests and that the severity of NAFLD increases in patients with higher body-mass index and triglyceride concentrations, as well as in patients with diabetes, hypertension, and insulin resistance. These patients also have a higher risk of all-cause mortality, mainly caused by an increased risk of cardiovascular events. Previously published data, however, as well as their own experience, suggested that statins were safe in patients with NAFLD.

Despite this, physicians can practice medicine defensively, said Mikhailidis, and might be reluctant to prescribe statins to patients with elevated liver enzymes at baseline. The purpose of the post hoc analysis was to assess the risk/benefit ratio in GREACE patients treated with a statin who had moderately abnormal liver tests, defined as serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) less than three times the upper limit of normal (<3x ULN).

In total, 227 patients were treated with statins, typically atorvastatin (Lipitor, Pfizer), over the three-year study. Statin therapy reduced baseline low-density lipoprotein cholesterol levels from 170 mg/dL to 95 mg/dL, as well as significantly reduced total cholesterol and triglyceride levels. Measures of liver function were also significantly improved, with ALT and AST concentrations reduced 35% and 47%, respectively. In a control cohort of 210 patients not treated with statins, lipid levels were unchanged, while liver-function tests showed increased ALT and AST concentrations.

In terms of cardiovascular morbidity, fewer patients with impaired liver-function tests treated with a statin had a cardiovascular event--nonfatal MI, revascularization, unstable angina, and congestive heart failure, as well as stroke and all-cause mortality--when compared with impaired liver-function-test patients who did not receive a statin. After three years, the event rate was 9.7%, or 3.2 events per 100-patient years, among the statin-treated patients, compared with 30.0%, or 10.0 cardiovascular events per 100-patient years, among those not treated with a statin.

Speaking with heartwire , Mikhailidis said the relative benefit among patients with mildly to moderately elevated liver-function tests was greater than that observed among patients with normal liver-function tests at baseline. For example, in those with normal ALT and AST concentrations at baseline, the relative reduction in cardiovascular events was 39%, compared with a 68% relative reduction in cardiovascular risk among those with mild to moderate elevations in liver enzymes.

Despite the results, Mikhailidis said there are important limitations to the study. "You have to remember, the numbers are small, with just 200 patients or so in each arm, and the duration is short, at three years," he said. "Most important of all, it's a post hoc analysis. You have to be very, very careful in post hoc analyses that you don't go about finding things and then proclaiming something huge. All of these factors are a considerable disadvantage, or weakness, in our conclusions."

Still, Mikhailidis told heartwire the data confirm the elevated risk of cardiovascular events among patients with NAFLD and hopes the work triggers similar post hoc analyses of the larger statin trials.

Statin-Induced Hepatotoxicity a Myth

In his editorial, Bader said that statin-induced liver toxicity is a myth, one that is fueled by the language in the package insert of the drugs. Large studies have shown no difference in the frequency or degree of ALT increases between treatment and placebo groups, and there are no reports of chronic carriers of drug-induced liver damage from statins.

Bader stressed that an elevation in ALT does not represent a disease state, yet many US physicians are reluctant to prescribe a statin to patients with ALT increases even 1.5x ULN. The finding of improved liver function among the statin-treated patients confirms studies performed in hepatitis-C patients treated with statins, another group in whom doctors are reluctant to prescribe the lipid-lowering drugs, writes Bader.

The authors report no conflicts of interest. Bader reports a patent application with the University of Oklahoma for the use of statins in patients with viral hepatitis.


1.       Athyros VG, Tziomalos K, Gossios TD, et al. Safety and efficacy of long-term statin treatment for cardiovascular events in patients with coronary heart disease and abnormal liver tests in the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) Study: A post hoc analysis. Lancet 2010; DOI:10.1016/S0140-6736(10)61272-X. Available at:

2.       Bader T. Liver tests are irrelevant when prescribing statins. Lancet 2010; DOI:10.1016/S0140-6736(10)61272-X. Available at:

Additional Resource
The National Cholesterol Education Program provides ATP III Guidelines At-A-Glance Quick Desk Reference as a downloadable document.

Clinical Context

By inhibiting hepatic production of cholesterol, statin treatment helps reduce the risk for cardiovascular events including myocardial infarction and stroke. Rarely, statin use may cause the adverse effect of increased levels of liver enzymes or serum transaminases such as ALT. Although statins have not been linked to liver injury, a survey showed that half of US academic physicians would be reluctant to give a statin to a patient with an ALT level of more than 1.5 times ULN and that 10% to 30% of patients who could benefit from statins would be denied this treatment.

NAFLD, which affects up to one third of adults in the United States, Europe, and Japan, is the most common cause of high ALT levels. The safety and efficacy of long-term statin treatment is unclear in patients with NAFLD, who often have high cholesterol levels and an increased risk for cardiovascular disease.

Study Highlights

  • This was a post hoc analysis of the study population from GREACE, a prospective, intent-to-treat study performed at the Hippokration University Hospital in Thessaloniki, Greece.
  • With use of a computer-generated randomization list, 1600 patients with coronary heart disease were assigned to receive a statin or usual care, which could include statins.
  • At baseline, participants were younger than 75 years, with serum concentrations of low-density lipoprotein cholesterol at more than 2.6 mmol/L and triglyceride levels at less than 4.5 mmol/L.
  • The goal of this analysis was to determine whether long-term (3-year) statin therapy is safe and effective for patients with moderately abnormal liver test results, defined as serum ALT or AST concentrations at less than 3 times ULN.
  • The main endpoint of the post hoc analysis was risk reduction for first recurrent cardiovascular event in patients who had moderately abnormal liver test results and who were treated with statins vs those who did not receive statins.
  • Patients with alcohol-related liver disease and liver diseases other than NAFLD were excluded.
  • Risk reduction for these patients was compared vs that for patients with normal liver test results who were treated or not treated with a statin.
  • Of 437 patients with moderately abnormal baseline liver test results, possibly because of NAFLD, all 227 who were treated with a statin had substantial improvement in liver test results (P < .0001).
  • The statin used in most of these patients was atorvastatin 24 mg per day.
  • In the 210 patients who did not receive statin treatment, liver enzyme concentrations increased further.
  • There were 22 cardiovascular events among 227 patients with abnormal liver test results who received a statin (10%; 3.2 events per 100 patient-years) vs 63 among 210 patients with abnormal liver test results who did not receive a statin (30%; 10.0 events per 100 patient-years; 68% relative risk reduction, P < .0001).
  • The reduction in cardiovascular disease in patients receiving a statin was greater (P = .0074) than it was in patients with normal liver test results (90 [14%] events in 653 patients receiving a statin [4.6 per 100 patient-years] vs 117 [23%] in 510 patients not receiving a statin [7·6 per 100 patient-years]; 39% relative risk reduction, P < .0001).
  • Of 880 participants who received a statin, 7 (< 1%) discontinued statin treatment because of liver-related adverse effects (transaminase concentrations > 3 times ULN).
  • On the basis of these findings, the investigators concluded that for patients with mild to moderately abnormal liver test results potentially attributable to NAFLD, statin treatment is safe and can improve liver test results and reduce cardiovascular morbidity risk.
  • Long-term (3-year) statin treatment has a significant positive benefit-to-risk ratio in these patients.
  • Limitations of this study include those inherent in a post hoc analysis; and small number of patients with possible NAFLD, preventing use of backward stepwise regression analysis to show the exact reduction in cardiovascular events per international unit per liter reduction in liver test results.

Clinical Implications

  • In a post hoc analysis from GREACE, all patients with abnormal increases in AST or ALT concentrations of up to 3 times ULN who were given a statin had a significant improvement in liver test results at 3-year follow-up, whereas patients with abnormal liver test results who did not receive a statin had a further increase in liver enzyme concentrations during follow-up.
  • In a post hoc analysis from GREACE, statin treatment was associated with a significant 68% decrease in the risk for cardiovascular events in patients with abnormal liver test results, which was greater than the statin-related relative risk reduction in patients with normal liver test results.