STAT order: Should patients with chronic liver disease be prescribed statins to prevent fibrosis progression and hepatocellular carcinoma?
Authors: Juan G. Abraldes, Kelly W. Burak
Journal: Hepatology (2016)

Potential conflict of interest: Dr. Abraldes consults for Promethera, received grants from Gilead, and received speaker fees from Janssen. Dr. Burak consults for and is on the speakers' bureau of Gilead and Astellas. She consults for and received grants from Lupin. She is on the speakers' bureau of and received grants from Bayer. She consults for Janssen, BTG, AbbVie, and Merck. She received grants from Verlyx. See Article on page 47 Statins are cholesterol‐lowering drugs that reduce risk of cardiovascular events and are among the most widely prescribed drugs in the world. Statins have additional effects beyond lipid lowering, known as "pleiotropic effects,"1 which include an improvement in endothelial dysfunction, as well as antioxidant, ‐fibrotic, and ‐inflammatory properties. Because of these pleiotropic effects, statins are frequently assessed for drug repurposing. However, in most of these cases, the initial enthusiasm raised by observational studies has not been confirmed in subsequent randomized, clinical trials (RCTs),1 and, currently, the only accepted indications for these drugs remain dyslipidemia and cardiovascular prevention. The potential of statins for treating liver diseases looks more promising.1 In patients with cirrhosis, simvastatin decreases portal pressure,2 and a recent multicenter trial showed that simvastatin improved survival after an acute variceal bleeding.3 The results of these RCTs, along with additional evidence from observational studies, suggest that the pathogenic events in chronic liver disease (CLD) might be uniquely sensitive to the pleiotropic effects of statins. In the last few years, a number of observational studies have shown that statins might have beneficial effects in patients with hepatitis B and hepatitis C virus (HCV), preventing fibrosis progression and decreasing the incidence of hepatocellular carcinoma (HCC). In addition, statins could have a direct antiviral activity against HCV, improving the response to interferon (IFN)‐based therapies. This antiviral effect is less relevant today with the availability of direct‐acting antiviral therapies for HCV, with sustained viral response (SVR) approaching 100%; however, statins might still have a role given that SVR significantly decreases, but does not eliminate, the risk of disease progression and HCC. Further adding to this evidence, in this issue of Hepatology Simon et al.4 revisit the ERCHIVES cohort, which included all HCV‐positive patients from Veterans Affiars centers across the United States between 2001 and 2014. As in their previous study,5 the investigators selected patients who received treatment for HCV, most with pegylated IFN and ribavirin, and excluded coinfected patients and those with cirrhosis at baseline. The most frequently used statin was simvastatin, followed by atorvastatin and pravastatin. The three outcomes assessed were progression in liver fibrosis assessed by the change in FIB‐4 score (which includes age, aspartate aminotransferase [AST], alanine aminotransferase [ALT], and platelet count), development of cirrhosis (defined by a FIB‐4 score ≥3.5), and incidence of HCC. Treatment with statins decreased fibrosis progression, incidence of cirrhosis, and incidence of HCC. Though this finding is not new, the present study does add some additional information. First, although statins improved rates of SVR, the preventive effect of statins was equally strong in patients not achieving SVR. Second, the chemopreventive effect against development of HCC was independent of the effect on fibrosis progression. Third, the beneficial effects of statins were dose dependent, and statin specific, mainly with atorvastatin and fluvastatin. Nonrandomized observational studies are notoriously prone to bias, although the present study has several strengths that enhance the association between statins and reduction of fibrosis and HCC risk. The cohort of patients comes from a well‐curated database of patients, and because the controls come from the same population as the cases, there is a lower risk of selection bias. Importantly, they had broad phenotypic information on subjects, allowing the investigators to adjust for multiple potential confounders.6 Finally, the investigators provided data to support a dose response, which further strengthens the association. However, the study also has significant limitations, and we must question the robustness of this dose‐response data and whether atorvastatin and fluvastatin should be considered superior to the other statins. Because different statins are used at different doses, the investigators used the cumulative defined daily dose (cDDD) received by each patient to globally assess the effect of dose. The defined daily dose (DDD) is defined by the World Health Organization (WHO) as the assumed average maintenance dose per day for a drug used for its main indication. For example, the WHO defines the DDD of atorvastatin as 20 mg. If a patient received 10 mg daily of atorvastatin for 4 years, the cDDD would be the same as for a patient receiving 40 mg daily for 1 year. Therefore, the association between cDDD and the outcomes might reflect both dose and duration. Further analysis may elucidate whether treatment duration, or indeed the dose of statins (which is normally titrated to cholesterol reduction), is more relevant to prevent liver outcomes. The other question raised by this study is whether positive effects of statins are a class effect, or whether they are limited to atorvastatin and fluvastatin. In the cardiovascular arena, it is well established that the benefits of statins are a class effect, and differences between statins are mainly related to the intensity of their cholesterol‐lowering effect, interactions, and pharmacokinetics. Several points need consideration in the present study. First, of their three endpoints under analysis, results for individual statins are only shown for fibrosis progression. No data are presented on the effects of individual statins on risk of cirrhosis (defined as reaching a FIB‐4 >3.5) or on risk of HCC. This should be subsequently reported given that it may help guide both clinicians and researchers on the choice of statins for future clinical trials. Second, the readout for assessing the effects of individual statins was the difference between the last measured and baseline FIB‐4. The interpretation of this value is incomplete without knowing the time interval between the two FIB‐4 values. Because Fib‐4 includes age in its calculation, if this interval was different for each of the statins, a systematic bias would be introduced. In addition, the mean changes in FIB‐4 shown for each statin were not adjusted by the other confounding factors, leaving it prone to the biases mentioned above. The adjusted P value of the comparison (0.04) only tells us that there was an overall difference between all groups, but not between each particular statin and the control group. Last, a different effect between statins on AST and ALT (which would impact FIB‐4 calculations) cannot be excluded. It is difficult to think that simvastatin, which was the most commonly used statin in this and other studies,7 had no beneficial effect on fibrosis while contributing to the overall global effect of statins. Therefore, only including atorvastatin and fluvastatin in the article title may be somewhat misleading, and unfair to other statins, specifically simvastatin. Although the study population was comprised of HCV individuals, statins were prescribed to treat hyperlipidemia, rather than as a possible antifibrotic or chemopreventive agent. Many patients had risk factors associated with metabolic syndrome and therefore could have coexisting nonalcoholic fatty liver disease (NAFLD). Although strong data are still lacking,8 it cannot be excluded that the benefit of statins could have occurred through improving NAFLD. Finally, statins appear to be safe and well tolerated, even in patients with CLD,9 but they do remain an important cause of drug‐induced liver injury (DILI). A registry of postmarketing adverse drug reactions in Sweden has found that DILI occurs in 1.6 per 100,000 statin users (fluvastatin 17, atorvastatin 2.9, and simvastatin at 0.9 per 100,000).10 The U.S. Food and Drug Administration recommends baseline testing of liver tests, but no longer recommends routine monitoring after initiation of statins. In summary, at this point, there is little doubt that patients with CLD with "cardiovascular indications" should be treated with a statin. However, the extension of the use of statins to patients without this indication requires conducting RCTs, which would need to be large and have significantly long periods of follow‐up to capture a reduction in clinically meaningful events. On the choice of statin, and the potential relevance of dosing, the current study provides some hints, but not definitive answers. Author names in bold designate shared co‐first authorship.