Statins for non-alcoholic fatty liver disease and non-alcoholic steatohepatitis

Cochrane database of systematic reviews (Online) (Impact Factor: 6.03). 12/2013; 12(12):CD008623. DOI: 10.1002/14651858.CD008623.pub2
Source: PubMed


Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are common causes of elevated liver enzymes in the general population. NASH and to some extent NAFLD have been associated with increased liver-related and all-cause mortality. No effective treatment is yet available. Recent reports have shown that the use of hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) in patients with elevated plasma aminotransferases may result in normalisation of these liver enzymes. Whether this is a consistent effect or whether it can lead to improved clinical outcomes beyond normalisation of abnormal liver enzymes is not clear.
To assess the beneficial and harmful effects of statins (that is, lovastatin, atorvastatin, simvastatin, pravastatin, rosuvastatin, and fluvastatin) on all-cause and liver-related mortality, adverse events, and histological, biochemical, and imaging responses in patients with NAFLD or NASH.
We performed a computerised literature search in the Cochrane Hepato-Biliary Group Controlled Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, and Science Citation Index Expanded up to March 2013. We did fully recursive searches from the reference lists of all retrieved relevant publications to ensure a complete and comprehensive search of the published literature. We did not apply any restrictions regarding language of publication or publication date.
All randomised clinical trials using statins as the primary treatment for NAFLD or NASH versus no treatment, placebo, or other hypolipidaemic agents.
Data were extracted, and risk of bias of each trial was assessed independently by two or more review authors. Meta-analyses were performed whenever possible. Review Manager 5.2 was used.
When the described search method was used and the eligibility criteria of the search results were applied, 653 records were found. Only two of these were randomised clinical trials that were considered eligible for inclusion. We assessed both trials as trials with high risk of bias. One of the trials was a pilot trial in which 16 participants with biopsy-proven NASH were randomised to receive simvastatin 40 mg (n = 10) or placebo (n = 6) once daily for 12 months. No statistically significant improvement in the aminotransferase level was seen in the simvastatin group compared with the placebo group. Liver histology was not significantly affected by simvastatin.The other trial had three arms. The trial compared atorvastatin 20 mg daily (n = 63) versus fenofibrate 200 mg daily (n = 62) versus a group treated with a combination of the two interventions (n = 61). There were no statistically significant differences between any of the three intervention groups regarding the week 54 mean activity levels of aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transpeptidase, and alkaline phosphatase. The triglyceride levels seemed higher in the fenofibrate group compared with the atorvastatin group. Liver histology was not assessed in this trial. The presence of biochemical and ultrasonographic evidence of NAFLD seemed to be higher in the fenofibrate group compared with the atorvastatin group (58% versus 33%). Three patients discontinued treatment due to myalgia and elevated serum creatine kinase activity; one from the atorvastatin group and two from the combination group. Another patient from the atorvastatin group discontinued treatment due to alanine aminotransferase activity that was over three times the upper normal limit.No data for all-cause mortality and hepatic-related mortality were reported in the included trials.
Based on the findings of this review, which included two trials with high risk of bias and a small numbers of participants, it seems possible that statins may improve serum aminotransferase levels as well as ultrasound findings. Neither of the trials reported on possible histological changes, liver-related morbidity or mortality. Trials with larger sample sizes and low risk of bias are necessary before we may suggest statins as an effective treatment for patients with NASH. However, as statins can improve the adverse outcomes of other conditions commonly associated with NASH (for example, hyperlipidaemia, diabetes mellitus, metabolic syndrome), their use in patients with non-alcoholic steatohepatitis may be justified.

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Available from: Reza Malekzadeh, Jan 31, 2014
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    • "In keeping with a possible beneficial effect of statins on the progression of liver disease related to fatty liver, Authors point out that in previous randomized trials statin administration decreased liver enzymes in patients with high serum aminotransferases at baseline [5]. Furthermore, statins effectively reduced cardiovascular events [6]. "

    Full-text · Article · Oct 2015 · Journal of Hepatology
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    • "A prospective study is unlikely now that nearly all statins are off patent and a meta-analyses concluded that statins may improve serum ALT or AST activity as well as ultrasound findings in NASH [6]. However, it is unlikely that a definite positive (or negative) result can be obtained from a meta-analysis, because the effect of statins may be complex (e.g. "
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    ABSTRACT: Nonalcoholic fatty liver disease (NAFLD) is the most frequent cause of elevated transaminase levels and affects approximately one third of the general population. Patients with NAFLD are at increased risk for cardiovascular events, which represent the leading cause of death in this population. We discuss the safety and efficacy of statins in this population. We reviewed the most recent literature on the safety of statins in patients with NAFLD and on their effects on liver histology and cardiovascular events. It appears that statins can be safely administered to patients with NAFLD, including those with elevated transaminase levels (<3 times the upper limit of normal). Post-hoc analyses of randomized controlled trials also suggest that statins might reduce cardiovascular morbidity in this population. On the other hand, there are few and controversial data on the effects of statins on liver histology in patients with NAFLD. Statins appear to be safe and might also reduce cardiovascular events in patients with NAFLD. Ongoing and future studies will clarify whether statins might also have a role in the treatment of NAFLD. Copyright © 2015. Published by Elsevier Inc.
    Full-text · Article · Jul 2015 · Metabolism: clinical and experimental
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    • "In the same vein, it was reported that statins, which are inhibitors of hydroxymethylglutarylcoenzyme A reductase, might be a valid therapeutic option to decrease intrahepatic cholesterol and to improve the abnormal metabolism of lipids [85]. In a well-written review that was published last year, Eslami et al. [86] reported that only two studies concerned the Table 6 "
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    ABSTRACT: Nonalcoholic steatohepatitis has become one of the most common liver-related health problems. This condition has been linked to an unhealthy diet and weight gain, but it can also be observed in nonobese people. The standard of care is represented by the lifestyle intervention. However, because this approach has several limitations, such as a lack of compliance, the use of many drugs has been proposed. The first-line pharmacological choices are vitamin E and pioglitazone, both showing a positive effect on transaminases, fat accumulation, and inflammation. Nevertheless, vitamin E has no proven effect on fibrosis and on long-term morbidity and mortality and pioglitazone has a negative impact on weight. Other drugs have been studied such as metformin, ursodeoxycholic acid, statins, pentoxiphylline, and orlistat with only partially positive results. Among the emerging treatments, telmisartan is particularly interesting as it seems to have an impact on insulin resistance, liver steatosis, inflammation, and fibrosis. However, the pathogenesis of steatohepatitis is highly complex and is determined by different parallel hits; indeed, the association of different drugs that act on various levels has been suggested. In conclusion, lifestyle intervention should be optimised and the associations of different drugs should be tested in large studies with long-term outcomes.
    Full-text · Article · Mar 2015 · Gastroenterology Research and Practice
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