Statins are used for both primary and secondary prevention of coronary artery disease. Multiple studies have shown liver-related adverse effects with raised concentrations of serum transaminases, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) with statin therapy.1 However, the use of statins in patients with raised transaminase enzymes (LFTs) due to non-alcoholic fatty liver disease (NAFLD) have shown improved liver histology and decreases in enzymes. The most common cause of elevated liver enzymes in the developed world is NAFLD.2 Its prevalence increases with age, body mass index, and high triglycerides. Furthermore, patients diagnosed with diabetes mellitus or hypertension are at increased risk of developing NAFLD. Patients who have NAFLD have a 69% increased chance of mortality due to cardiovascular disease.3 NAFLD treatment includes lifestyle modifications, such as dietary changes and exercise, or pharmacotherapy interventions. Statins have been used in the treatment of NAFLD. However, no study has been able to determine the risk-to-benefit ratio of statins in this population.
A post-hoc analysis of the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) study explored the safety and efficacy of statin treatment in patients with abnormal liver tests.4 Subjects (< 75 years of age, known coronary artery disease, serum LDL > 2.6 mmol/L or 100 mg/dl, and triglycerides < 4.5 mmol/L or 174 mg/dL) were randomized to either statin therapy or usual care, which could include statins. Exclusion of participants involved those whose lifestyle could directly result in an increase in liver enzymes, such as alcohol misuse or chronic hepatitis B or C. Patients with liver enzyme concentrations above three times the upper limit of normal were also excluded from the study. The primary endpoint of the post-hoc analysis was the first occurrence of any cardiovascular event (all-cause mortality, coronary heart disease mortality and morbidity, or stroke) in those patients with abnormal LFTs who were treated with a statin compared with patients who did not receive a statin. Secondary endpoints were effects of statin therapy on LFTs in patients with abnormal baseline liver tests. The average follow-up time for participants was about three years.
There was a significant decrease in the incidence of cardiovascular events in the 227 patients with abnormal liver tests (< three times upper limit of normal) on statin therapy, compared to the 210 patients on no statin therapy (68% risk reduction, p<0.0001). The magnitude of benefit was greater than in those seen in patients with normal LFTs while receiving a statin (p=0.0074). In patients with elevated baseline LFTs, statin therapy was associated with a significant decrease in enzymes compared to patients not receiving statin therapy (p<0.0001). In contrast, patients with abnormal baseline tests and not on statin therapy exhibited increases in liver enzyme concentrations.
There appears to be a significant positive benefit-to-risk ratio with long term treatment of statins in patients with NAFLD and elevated liver enzymes. Statin therapy reduces elevated levels of liver enzymes and cardiovascular-related mortality and morbidity.
1. Newman C, Tsai J, Szarek M, Luo D, Gibson E. Comparative safety of atorvastatin 80 mg versus 10 mg derived from analysis of 49 completed trials in 14,236 patients. Am J Cardiol
2. Ramesh S, Sanval AJH. Evaluation and management of non-alcoholic steatohepatitis. J Hepat
3. Soderberg C, Stal P, Askling J, et al. Decreased survival of subjects with elevated liver function tests during a 28-year follow-up. Hepatology 2010;51: 595–602.
4. 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 Atovastatin and Coronary Heart Disease Evaluation (GREACE) Study: a post-hoc analysis. The Lancet