We thank our colleagues for the timely letter, giving us the opportunity to underline a point which was not considered in our review Citation[1], i.e., the tight control of cholesterol levels and cardiovascular risk by statins.
Several recent studies suggested that elevated liver enzymes (namely alanine aminotransferase and particularly γ-glutamyl-transpeptidase levels Citation[2]) are significantly associated with cardiovascular risk, independent of established risk factors and the features of the metabolic syndrome. This evidence fits with the results of the GREACE study, where atorvastatin treatment in subjects with coronary disease and abnormal liver tests reduced both cardiovascular events and liver enzymes Citation[3].
Unfortunately, when statins were used to reduce fatty liver, the results were disappointing. In a comprehensive meta-analysis, Musso et al. identified 4 RCT of statin use in NAFLD Citation[4]. In the only study based on repeated liver biopsies, simvastatin did not improve histological outcomes; in the remaining studies atorvastatin improved the ultrasonographic imaging of the liver and/or liver enzymes, as biochemical markers of steatosis. In the large St. Francis Heart Study, atorvastatin combined with vitamin E and C significantly reduced the odds of NAFLD in a 3.6-year follow-up Citation[5]. Ezetimibe was evaluated in 2 uncontrolled trials and 2 RCTs, consistently improving liver histology and plasma lipids Citation[4]. Notably all studies reported that statins were well-tolerated Citation[6], confirming the results of Chalasani et al. that patients with elevated liver enzymes are not at higher risk for statin hepatotoxicity Citation[7].
Triglyceride accumulation in the liver should no longer be considered a mere epiphenomenon of the dyslipidemia associated with insulin resistance, but steatosis probably participates in the metabolic imbalance and drives an additional cardiovascular risk. A comprehensive management of NAFLD must include an effective drug treatment of hyperlipidemia to reduce both liver disease progression and cardiovascular-related outcomes, and statins may be a valuable opportunity.
Declaration of interest
G Marchesini has received honoraria from Sanofi and Roche. All other authors have nothing to declare.
Bibliography
- Moscatiello S, Di Luzio R, Sasdelli AS, Managing the combination of nonalcoholic fatty liver disease and metabolic syndrome. Expert Opin Pharmacother 2011;13:2657-72
- Fraser A, Harris R, Sattar N, Gamma-glutamyltransferase is associated with incident vascular events independently of alcohol intake: analysis of the British Women's Heart and Health Study and Meta-Analysis. Arterioscler Thromb Vasc Biol 2007;27:2729-35
- Athyros VG, Tziomalos K, Gossios TD, 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;376:1916-22
- Musso G, Cassader M, Gambino R. Cholesterol-lowering therapy for the treatment of nonalcoholic fatty liver disease: an update. Curr Opin Lipidol 2011;22:489-96
- Foster T, Budoff MJ, Saab S, Atorvastatin and antioxidants for the treatment of nonalcoholic fatty liver disease: the St Francis Heart Study randomized clinical trial. Am J Gastroenterol 2011;106:71-7
- Riley P, Al Bakir M, O'Donohue J, Prescribing statins to patients with nonalcoholic fatty liver disease: real cardiovascular benefits outweigh theoretical hepatotoxic risk. Cardiovasc Ther 2009;27:216-20
- Chalasani N, Aljadhey H, Kesterson J, Patients with elevated liver enzymes are not at higher risk for statin hepatotoxicity. Gastroenterology 2004;126:1287-92