Is there a role of lipid-lowering therapies in the management of fatty liver disease?

Abstract

Atherogenic dyslipidemia is characterized by increased triglyceride-rich lipoproteins and low high-density lipoprotein cholesterol concentrations. It is highly prevalent in non-alcoholic fatty liver disease (NAFLD) and contributes to the increased cardiovascular risk associated with this condition. Alongside insulin resistance it plays an important pathogenetic role in NAFLD/non-alcoholic steatohepatitis (NASH) development and progression. It has been shown that cholesterol-lowering reduces cardiovascular risk more in NAFLD vs non-NAFLD high-risk individuals. This evidence highlights the importance of effective lipid modulation in NAFLD. In this narrative review the effects of the most commonly used lipid-lowering therapies on liver outcomes alongside their therapeutic implications in NAFLD/NASH are critically discussed. Preclinical and clinical evidence suggests that statins reduce hepatic steatosis, inflammation and fibrosis in patients with NAFLD/NASH. Most data are derived from observational and small prospective clinical studies using changes in liver enzyme activities, steatosis/fibrosis scores, and imaging evidence of steatosis as surrogates. Also, relevant histologic benefits were noted in small biopsy studies. Atorvastatin and rosuvastatin showed greater benefits, whereas data for other statins are scarce and sometimes conflicting. Similar studies to those of statins showed efficacy of ezetimibe against hepatic steatosis. However, no significant anti-inflammatory and anti-fibrotic actions of ezetimibe have been shown. Preclinical studies showed that fibrates through peroxisome proliferator-activated receptor (PPAR)α activation may have a role in NAFLD prevention and management. Nevertheless, no relevant benefits have been noted in human studies. Species-related differences in PPARα expression and its activation responsiveness may help explain this discrepancy. Omega-3 fatty acids reduced hepatic steatosis in numerous heterogeneous studies, but their benefits on hepatic inflammation and fibrosis have not been established. Promising preliminary data for the highly purified eicosapentaenoic acid require further confirmation. Observational studies suggest that proprotein convertase subtilisin/kexin9 inhibitors may also have a role in the management of NAFLD, though this needs to be established by future prospective studies.

Keywords: Non-alcoholic fatty liver, Non-alcoholic steatohepatitis, Statin, Ezetimibe, Fibrates, ω-3 fatty acids, Bile acid resins

Core Tip: Statins may be beneficial against non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) in association with their cholesterol-lowering efficacy as well as their anti-inflammatory, antioxidant and anti-fibrotic actions. Elimination of hepatic steatosis, inflammation and fibrosis was noted with statin use in the clinical setting of NAFLD/NASH. Experimental evidence suggests that ezetimibe has similar benefits to statins against NAFLD/NASH. However, ezetimibe was beneficial only against hepatic steatosis, but not against inflammation or fibrosis in NAFLD patients. Despite their promising mechanistic potential against NAFLD/NASH through PPARα activation benefits of fibrates on liver outcomes have not been established in clinical studies. Ample heterogeneous evidence suggests benefits of ω-3 fatty acids against hepatic steatosis, but not inflammation or fibrosis.