Statins in liver disease: not only prevention of cardiovascular events

KEYWORDS:

• Fatty liver
• cardiovascular risk
• hydroxymethylglutaryl-CoA reductase inhibitors
• non-alcoholic fatty liver disease
• fatty liver
• drug safety

Statins are lipid-lowering agents and one of the most prescribed drugs worldwide. Their main mechanism of action – inhibition of the mevalonate pathway through an effect on hydroxy-methylglutaryl CoA reductase, thus affecting the synthesis of cholesterol in the liver – makes this class of drugs pivotal in primary and secondary prevention of cardiovascular risk, as extensively demonstrated in large prospective, randomized controlled trials. Along the years, we learned that the lower the better, and LDL-cholesterol targets have been progressively reduced to values ≤70 mg/dL for secondary prevention or in the presence of diabetes.

The use of statins in patients with liver disease has long been limited by concern for their potential hepatotoxicity, raised by anecdotal evidence of raised liver enzymes following their use, or possible trapping of lipids in the liver. Statins metabolism occurs in the liver and statin intake has been associated with higher transaminase levels [1]. In 2006, an extensive analysis of the Dallas Heart Study suggested that no harm was to be expected for the use of statins in subjects with liver disease, also including patients with hepatic steatosis [2], and in a large practice-based analysis, patients with elevated liver enzymes were not at higher risk of statin hepatotoxicity [3]. In a comprehensive review, Bjornsson et al. reported that statin-related adverse events are very rare, although potentially severe. Both atorvastatin and simvastatin were associated with fatal outcomes, whereas no fatality was reported with rosuvastatin, suggesting a safer profile of novel statins [4]. This analysis was further supported by a Cochrane Systematic Review in 2013, confirming that statins should be used, independently of any underlying liver disease, since the control of cardiovascular risk remains pivotal to reduce comorbidity [5]. This is mainly the case of subjects with both alcoholic and nonalcoholic fatty liver disease (AFLD and NAFLD), frequently associated with the metabolic syndrome and cardiovascular risk.

Several prospective studies and meta-analyses followed to support a more extensive use of statins, particularly in the NAFLD area. In the present issue of Expert Review of Gastroenterology & Hepatology, Imprialos et al. review the available evidence about statins and NAFLD, discussing the positive effects, possibly outweighing the reduction in cardiovascular risk and moving statins as a possible therapeutic option for liver disease itself [6]. A few comments about this relevant issue might be of interest.

Nonalcoholic fatty liver, i.e. the accumulation of lipids in hepatocytes above the physiologic threshold of 5% in the absence of significant alcohol intake (limits: 20 g/day in females, 30 g/day in males), occurs in nearly 25% of adults worldwide, but in nearly 75% of subjects with obesity and over 50% of cases with type 2 diabetes [7]. In approximately 10% of cases with fatty liver the disease progresses to hepatic necroi\nflammation and fibrosis (nonalcoholic steatohepatitis – NASH), cirrhosis (NASH – cirrhosis), and eventually to hepatocellular carcinoma (HCC). The overall prevalence of disease is expected to increase further, due to the obesity epidemics, and NAFLD is now the second leading cause of liver transplantation in the United States [8]. However, in long-term follow-up studies, fatal cardiovascular events are the most common causes of NASH-related mortality [9], driven by type 2 diabetes mellitus (T2DM), metabolic syndrome, with increased levels of small dense atherogenic lipoprotein subfractions [10] and diffuse atherosclerotic lesions [11], and requiring intensive treatment. This is the rationale for statin use in this population, but what about their effects on the liver?

The initial evidence for a beneficial effect of statins on liver function came from epidemiological studies, where statin use was associated with reduced risk of ultrasonography- and/or histologically-assessed NAFLD/NASH [12,13], also in the presence of diabetes, where the use of statins reduced the risk of both NASH and severe fibrosis [14]. Atorvastatin reduced the expression of perilipin 5 in hepatocytes, contributing to increased lipolysis and reduced triglyceride accumulation through protein kinase A phosphorylation [15]. A systematic review and meta-analysis confirmed that statins were associated with lower risk of advanced liver disease and mortality, and might also reduce portal hypertension, stopping disease progression and even promoting fibrosis regression [16]. Simvastatin acted as Krüppel-like factor 2 inducer, improving cell viability, ameliorating liver injury in ischemia/reperfusion and improving fibrosis, endothelial dysfunction and portal hypertension in both animal and human models of liver sinusoidal endothelial and stellate cells [17,18]. Acute pretreatment with simvastatin of the donor protected liver tissue and cells during cold storage for posterior transplantation [19]. The pleiotropic effects of statins also extend to anti-fibrotic action, as well as to better response to treatment for chronic hepatitis C and reduced risk and better survival rate of hepatocellular carcinoma [20]. Unfortunately, only few and limited studies were specifically designed to test the use of statins in the treatment of NAFLD and were inconclusive. Larger studies would be difficult to arrange, particularly in diabetes-associated NAFLD, considering that the use of statins carries an increased risk of new onset diabetes [21]. Several novel drugs are on the horizon for treatment in NAFLD/NASH, and are being tested in phases 2–3 trials in subjects with/without diabetes in order to reduce hepatic necroinflammation, without worsening of fibrosis [22]. No matter they may be confidently associated with statins to achieve better hepatic and cardiovascular outcomes. NAFLD Clinical Practice Guidelines, jointly published by the European Associations of Liver Disease, Diabetes and Obesity (EASL-EASD-EASO) strongly recommend strict control of cardiovascular risk in patients with NAFLD/NASH [23], and statins remain a safe, effective and pivotal therapeutic option to this goal.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

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Funding

This paper was not funded.