Are statins a remedy for all seasons?
Authors: Francesco Negro
Journal: Journal of Hepatology (2014)

Statin use is associated with a reduced risk of fibrosis progression in chronic hepatitis CJournal of HepatologyVol. 62Issue 1PreviewHepatitis C virus (HCV) is one of the most common causes of chronic liver disease and the leading indication for liver transplantation worldwide [1,2]. Chronic hepatitis C (CHC) leads to cirrhosis and hepatocellular carcinoma (HCC). Estimates suggest that over a period of twenty to thirty years, cirrhosis will develop in 10% to 25% of patients with CHC, and HCC will develop in 1% to 5% [2]. Although the success of HCV therapy now improved with the introduction of direct-acting antiviral medications, there are still many patients with advanced fibrosis in whom disease progression may nevertheless occur, despite successful viral clearance. Full-Text PDF The hepatitis C virus (HCV) is a major cause of chronic liver disease, infecting ∼185,000,000 persons, i.e. ∼2.8% of the world population, and causing 350,000 deaths annually [[1]Hajarizadeh B. Grebely J. Dore G.J. Epidemiology and natural history of HCV infection.Nat Rev Gastroenterol Hepatol. 2013; 10: 553-562Crossref PubMed Scopus (793) Google Scholar]. Chronic hepatitis C relentlessly leads to increasing degrees of fibrosis and ultimately cirrhosis. The fibrosis progression rate is variable, with some patients progressing to cirrhosis within a few years, while others may never progress even after decades from infection, depending on the presence and type of host, viral and environmental factors [[2]Rüeger S, Bochud PY, Dufour JF, Muellhaupt B, Semela D, Heim MH, et al. Impact of common risk factors of fibrosis progression in chronic hepatitis C. Gut [in press].Google Scholar]. Although many of these factors cannot be modified [[2]Rüeger S, Bochud PY, Dufour JF, Muellhaupt B, Semela D, Heim MH, et al. Impact of common risk factors of fibrosis progression in chronic hepatitis C. Gut [in press].Google Scholar], the fibrosis progression of hepatitis C can be effectively stopped with potent antivirals, leading to HCV eradication [[3]D'Ambrosio R. Aghemo A. Rumi M.G. Ronchi G. Donato M.F. Paradis V. et al.A morphometric and immunohistochemical study to assess the benefit of a sustained virological response in hepatitis C virus patients with cirrhosis.Hepatology. 2012; 56: 532-543Crossref PubMed Scopus (338) Google Scholar]. On the other hand, modification of the natural history of hepatitis C, by modulating the fibrogenic process, independently of any intervention on HCV, has so far been a chimera, despite intense preclinical research efforts. More in general, the clinical development of antifibrotics has been lagging behind, and no effective drugs have been validated in the clinical setting [[4]Schuppan D. Pinzani M. Anti-fibrotic therapy: lost in translation?.J Hepatol. 2012; 56: S66-S74Abstract Full Text PDF PubMed Scopus (96) Google Scholar]. Statins may have some antifibrotic activity in pulmonary [[5]Watts K.L. Sampson E.M. Schultz G.S. Spiteri M.A. Simvastatin inhibits growth factor expression and modulates profibrogenic markers in lung fibroblasts.Am J Respir Cell Mol Biol. 2005; 32: 290-300Crossref PubMed Scopus (104) Google Scholar] and cardiac [[6]Reddy R. Chahoud G. Mehta J.L. Modulation of cardiovascular remodeling with statins: fact or fiction?.Curr Vasc Pharmacol. 2005; 3: 69-79Crossref PubMed Scopus (30) Google Scholar] fibrosis, although the mechanisms of these purported beneficial effects are undefined. Furthermore, there is some limited evidence on the antifibrotic effect of statins in experimental rat models of liver fibrosis [7Trebicka J. Hennenberg M. Odenthal M. Shir K. Klein S. Granzow M. et al.Atorvastatin attenuates hepatic fibrosis in rats after bile duct ligation via decreased turnover of hepatic stellate cells.J Hepatol. 2010; 53: 702-712Abstract Full Text Full Text PDF PubMed Scopus (189) Google Scholar, 8Miyaki T. Nojiri S. Shinkai N. Kusakabe A. Matsuura K. Iio E. et al.Pitavastatin inhibits hepatic steatosis and fibrosis in non-alcoholic steatohepatitis model rats.Hepatol Res. 2011; 41: 375-385Crossref PubMed Scopus (34) Google Scholar], while clinical trials in patients with non-alcoholic fatty liver disease have been discouraging [[9]Younossi Z.M. Reyes M.J. Mishra A. Mehta R. Henry L. Systematic review with meta-analysis: non-alcoholic steatohepatitis – A case for personalised treatment based on pathogenic targets.Aliment Pharmacol Ther. 2014; 39: 3-14Crossref PubMed Scopus (77) Google Scholar]. Simon et al. [[10]Simon T.G. King L.Y. Zheng H. Chung R.T. Statin use is associated with a reduced risk of fibrosis progression in chronic hepatitis C.J Hepatol. 2015; 62: 18-23Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar] analysed the association between statin use and liver fibrosis progression in a well-characterized cohort of chronic hepatitis C patients enrolled in the HALT-C trial [[11]Di Bisceglie A.M. Shiffman M.L. Everson G.T. Lindsay K.L. Everhart J.E. Wright E.C. et al.Prolonged therapy of advanced chronic hepatitis C with low-dose peginterferon.N Engl J Med. 2008; 359: 2429-2441Crossref PubMed Scopus (407) Google Scholar]. All patients had advanced liver fibrosis (Ishak fibrosis score ⩾3) at entry as well as a history of virological non-response to standard interferon therapies. After 24 weeks of retreatment with peginterferon alfa-2a and ribavirin, patients were randomized based on their virological response at week 20: those with detectable serum HCV RNA were assigned for the next 3.5 years to either a maintenance therapy with 90 μg of peginterferon alfa-2a weekly without ribavirin or to an untreated control group. One of the goals of this trial was to evaluate whether a low dose of interferon-alpha maintenance therapy could improve histological outcomes independently of antiviral effects [[11]Di Bisceglie A.M. Shiffman M.L. Everson G.T. Lindsay K.L. Everhart J.E. Wright E.C. et al.Prolonged therapy of advanced chronic hepatitis C with low-dose peginterferon.N Engl J Med. 2008; 359: 2429-2441Crossref PubMed Scopus (407) Google Scholar], by centrally assessing serial liver biopsies performed at enrolment and 1.5 and 3.5 years after randomization. In the study by Simon et al. [[10]Simon T.G. King L.Y. Zheng H. Chung R.T. Statin use is associated with a reduced risk of fibrosis progression in chronic hepatitis C.J Hepatol. 2015; 62: 18-23Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar], the use of statins was ascertained as part of a comprehensive medical history, obtained at enrolment and in the course of the study. Thus, a total of 543 patients with serial liver biopsies could be evaluated: 29 had received continuous statin therapy throughout the study, while 514 did not, thus serving as controls. Liver fibrosis progression occurred in 3 of 29 (10%) statin users and in 145 of 514 (29%) non-users. The hazard ratio for fibrosis progression among statin users compared to non-users was 0.31 (95% CI 0.10–0.97), after adjustment for a few of the known predictors of progression, such as body mass index, platelets and hepatic steatosis. In addition, the average change in the Ishak fibrosis score across the whole study period was −0.34 (SE 0.18) for statin users compared to +0.42 (SE 0.07) for non-users. Histological activity score or alanine aminotransferase level changes were not statistically different between statin users and non-users. The authors concluded that statin use is associated with a reduced risk of the liver fibrosis progression rate in chronic hepatitis C patients with advanced fibrosis, and that this beneficial effect does not appear to be mediated by a decrease in the level of liver inflammation. Statins are extensively used in clinical practice for both primary and secondary prevention of cardiovascular events in patients with coronary artery diseases, diabetes mellitus and other atherosclerotic disorders. Statins exert their effect primarily via inhibition of the 3-hydroxy-3-methylglutaryl-coenzyme A reductase, a transmembrane protein catalyzing a rate-limiting step in the mevalonate pathway that leads to the synthesis of isoprenoids and sterols. The major and best known effect of this inhibitory action is the reduction of circulating cholesterol. However, many beneficial effects of statins seem independent of cholesterol level reduction. These pleiotropic effects of statins include anti-inflammatory, immunomodulatory, antibacterial, antiproliferative, antioxidant effects as well as the improvement of endothelial function and the suppression of platelet aggregation (reviewed in [[12]Mihos C.G. Pineda A.M. Santana O. Cardiovascular effects of statins, beyond lipid-lowering properties.Pharmacol Res. 2014; 88C: 12-19Crossref Scopus (118) Google Scholar]). On one hand, pleiotropic effects of statins are still secondary to the blockade of the mevalonate synthesis. This leads in fact to an impaired production of lipophilic prenyl compounds, involved in the post-translational modification of several factors, such as some small GTP-binding proteins (e.g. Rho, Rac, and Ras) and other proteins, whose localization to cell membranes depends on their isoprenylation [6Reddy R. Chahoud G. Mehta J.L. Modulation of cardiovascular remodeling with statins: fact or fiction?.Curr Vasc Pharmacol. 2005; 3: 69-79Crossref PubMed Scopus (30) Google Scholar, 12Mihos C.G. Pineda A.M. Santana O. Cardiovascular effects of statins, beyond lipid-lowering properties.Pharmacol Res. 2014; 88C: 12-19Crossref Scopus (118) Google Scholar]. In addition, impaired sterol synthesis may alter the composition of rafts, thus interfering with cell signalling and apoptosis, which may account, in part, for their antitumour effects [[13]Clendening J.W. Penn L.Z. Targeting tumor cell metabolism with statins.Oncogene. 2012; 31: 4967-4978Crossref PubMed Scopus (182) Google Scholar]. Indeed, statins have been shown to reduce cancer-related mortality in several studies, including the vast survey on the Danish Civil Registration System database [[14]Nielsen S.F. Nordestgaard B.G. Bojesen S.E. Statin use and reduced cancer-related mortality.N Engl J Med. 2012; 367: 1792-1802Crossref PubMed Scopus (762) Google Scholar], and also to reduce the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis C [[15]Tsan Y.T. Lee C.H. Ho W.C. Lin M.H. Wang J.D. Chen P.C. Statins and the risk of hepatocellular carcinoma in patients with hepatitis C virus infection.J Clin Oncol. 2013; 31: 1514-1521Crossref PubMed Scopus (184) Google Scholar] or chronic hepatitis B [[16]Tsan Y.T. Lee C.H. Wang J.D. Chen P.C. Statins and the risk of hepatocellular carcinoma in patients with hepatitis B virus infection.J Clin Oncol. 2012; 30: 623-630Crossref PubMed Scopus (238) Google Scholar]. On the other hand, also mevalonate-independent mechanisms seem to be involved. For example, a recent, interesting study showed that statins increased small GTP-binding protein GDP dissociation simulator (SmgGDS) in cultured human endothelial cells [[17]Tanaka S. Fukumoto Y. Nochioka K. Minami T. Kudo S. Shiba N. et al.Statins exert the pleiotropic effects through small GTP-binding protein dissociation stimulator upregulation with a resultant Rac1 degradation.Arterioscler Thromb Vasc Biol. 2013; 33: 1591-1600Crossref PubMed Scopus (73) Google Scholar]. Adding prenyl compounds failed to counteract the SmgGDS increase. This effect explained the statin-associated protection against angiotensin II-induced medial thickening of coronary arteries and fibrosis in a mouse model [[17]Tanaka S. Fukumoto Y. Nochioka K. Minami T. Kudo S. Shiba N. et al.Statins exert the pleiotropic effects through small GTP-binding protein dissociation stimulator upregulation with a resultant Rac1 degradation.Arterioscler Thromb Vasc Biol. 2013; 33: 1591-1600Crossref PubMed Scopus (73) Google Scholar]. SmgGDS favours degradation of the intracellular factor Rac1, thus blocking its induction of reactive oxygen species and providing a mechanism whereby statins may reduce oxidative stress [[6]Reddy R. Chahoud G. Mehta J.L. Modulation of cardiovascular remodeling with statins: fact or fiction?.Curr Vasc Pharmacol. 2005; 3: 69-79Crossref PubMed Scopus (30) Google Scholar], an interesting observation that may in part explain the antifibrotic effect of statins. Concerning the latter, Simon et al. [[10]Simon T.G. King L.Y. Zheng H. Chung R.T. Statin use is associated with a reduced risk of fibrosis progression in chronic hepatitis C.J Hepatol. 2015; 62: 18-23Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar] discuss some potential, additional mechanisms, such as activation of the Kruppel-like factor 2 in endothelial cells, which may lead to an enhanced transcription of vasoprotective genes, but clearly the fine details linking statins and fibrogenesis warrant further work. The study of Simon et al. [[10]Simon T.G. King L.Y. Zheng H. Chung R.T. Statin use is associated with a reduced risk of fibrosis progression in chronic hepatitis C.J Hepatol. 2015; 62: 18-23Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar], although intriguing, has limitations as duly acknowledged by the authors. First, the low number of outcomes among statin users (3 out of 29) limited the ability to test for all potential confounders and the scope of the multivariable analysis that was conducted. Thus, these results should be considered as preliminary, and warrant a validation in additional studies with larger sample sizes and a greater number of outcomes. Second, the HALT-C trial included only patients with advanced liver fibrosis and in whom interferon was not contraindicated, i.e. a very selected population. More data is warranted in patients with milder fibrosis stages. Third, no dose effect could be assessed since the dose of statins used by study participants – a crucial parameter to assess a causal link with a clinical outcome – was not recorded. In addition, statins may have exerted their protective effect indirectly, i.e. via the suppression of HCV replication. Indeed, statins exert some degree of antiviral effect on HCV both in vitro and in vivo, especially when added to standard doses of interferon-α and ribavirin [[18]Verpaalen B. Neyts J. Delang L. Are statins a viable option for the treatment of infections with the hepatitis C virus?.Antiviral Res. 2014; 105: 92-99Crossref PubMed Scopus (13) Google Scholar]. However, when the authors analysed the change in viral load over the study period, the median decline in HCV RNA was comparable among statin users and non-users, even after adjustment for randomization to the treatment or observation group. This suggests that the low dose interferon used in HALT-C was probably insufficient to produce any meaningful antiviral effect, and that therefore the reduction of HCV replication could not be a confounder in their study. Another caveat that should caution against a wider use of statins consists of the fact that any purported beneficial effect should be carefully weighed against the potential side effects of a long term statin use. Although the reported cases of significant hepatotoxicity are rare [[19]Russo M.W. Hoofnagle J.H. Gu J. Fontana R.J. Barnhart H. Kleiner D.E. et al.Spectrum of statin hepatotoxicity: experience of the drug-induced liver injury network.Hepatology. 2014; 60: 679-686Crossref PubMed Scopus (173) Google Scholar], statins, particularly the lipophilic ones (simvastatin, lovastatin and the blockbuster atorvastatin), still present some safety concerns, such as the risk of myopathies, renal dysfunction, cognitive and behavioural dysfunction (including memory loss), and – possibly – the development of diabetes mellitus [[20]Katz D.H. Intwala S.S. Stone N.J. Addressing statin adverse effects in the clinic: the 5 Ms.J Cardiovasc Pharmacol Ther. 2014; ([Epub ahead of print])PubMed Google Scholar]. In addition, drug-drug interactions may limit their use in patients with several comorbidities [[20]Katz D.H. Intwala S.S. Stone N.J. Addressing statin adverse effects in the clinic: the 5 Ms.J Cardiovasc Pharmacol Ther. 2014; ([Epub ahead of print])PubMed Google Scholar]. Thus, as usual, a word of caution is mandatory before we draw firm conclusions. For a hepatologist's point of view, statins may well reduce the degree of portal hypertension [[21]Abraldes J.G. Albillos A. Banares R. Turnes J. Gonzalez R. Garcia-Pagan J.C. et al.Simvastatin lowers portal pressure in patients with cirrhosis and portal hypertension: a randomized controlled trial.Gastroenterology. 2009; 136: 1651-1658Abstract Full Text Full Text PDF PubMed Scopus (332) Google Scholar] and the risk of HCC in cirrhotic patients [15Tsan Y.T. Lee C.H. Ho W.C. Lin M.H. Wang J.D. Chen P.C. Statins and the risk of hepatocellular carcinoma in patients with hepatitis C virus infection.J Clin Oncol. 2013; 31: 1514-1521Crossref PubMed Scopus (184) Google Scholar, 16Tsan Y.T. Lee C.H. Wang J.D. Chen P.C. Statins and the risk of hepatocellular carcinoma in patients with hepatitis B virus infection.J Clin Oncol. 2012; 30: 623-630Crossref PubMed Scopus (238) Google Scholar], but for these indications and as antifibrotic agents we need more data. Nevertheless, the paper by Simon and collaborators has the great merit of providing the basis for prospective cohort validation studies and intriguing working hypotheses that may (or may not) make statins, already among the top selling drugs of all times, a true remedy for all seasons, given their numerous beneficial effects in several fields of medicine other than hepatology. FN is consultant for Roche and MSD, is advising Gilead, Janssen, Novartis, Bristol-Myers Squibb and Boehringer Ingelheim, and has received unrestricted research grants from Roche, Gilead and Novartis. I wish to thank Drs Sophie Clément, Emiliano Giostra, and Nicolas Goossens for critically reading the manuscript.