Treatment of Decompensated Cirrhosis Patients with Simvastatin: Why, Safety, Efficacy, Futility, and Learning
Main Article Content
Alberto E. Muñoz
http://orcid.org/0000-0002-5458-4692
M. Fernanda Veltens
http://orcid.org/0000-0002-5458-4692
M. Fernanda Veltens
Abstract
The article reviews the clinical experimental trials of simvastatin in cirrhosis. It will attempt to engage the reader in this interesting hepatic subject through the following four steps. Firstly, the paper explains the rationale for statins use, ranging from portal hypertension to decompensated cirrhosis. Secondly, the article summarizes the drug safety results (the relationship between liver/muscle injuries and simvastatin dosage/cirrhosis severity), and the efficacy outcomes (survival/quality of life improvements, and reduction of hospitalizations due to cirrhosis complications) in patients with the decompensated state. Thirdly, the paper analyzes the negative results of treating severe degrees of cirrhosis –Child-Pugh class C and acute-on-chronic liver failure, with this medication. Lastly, this article aims to summarize the lessons learned from the few clinical trials in simvastatin therapy on the decompensated stage. The paper will encourage readers to consider simvastatin as a potential treatment option for cirrhosis in the future.
Keywords:
Liver cirrhosis, Simvastatin, Nitric oxide, Inflammation, Fibrosis, Quality of life, Hospitalization
Article Details
How to Cite
MUÑOZ, Alberto E.; VELTENS, M. Fernanda.
Treatment of Decompensated Cirrhosis Patients with Simvastatin: Why, Safety, Efficacy, Futility, and Learning.
Medical Research Archives, [S.l.], v. 13, n. 10, oct. 2025.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/6958>. Date accessed: 05 dec. 2025.
doi: https://doi.org/10.18103/mra.v13i10.6958.
Section
Review Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
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7. Morgan S, Grootendorst P, Lexchin J, et al. The cost of drug development: a systematic review. Health Policy. 2011;100(1):4-17.
8. Lai AG, Chang WH, Parisinos CA, et al. An informatics consult approach for generating clinical evidence for treatment decisions. BMC Med Inform Decis Mak. 2021;21(1):281.
9. Bosch J. Vascular deterioration in cirrhosis: the big picture. J Clin Gastroenterol. 2007;41 Suppl 3:S247-53.
10. Bhathal PS, Grossman HJ. Reduction of the increased portal vascular resistance of the isolated perfused cirrhotic rat liver by vasodilators. J Hepatol. 1985;1(4):325-37.
11. Marteau P, Ballet F, Chazouilleres O, et al. Effect of vasodilators on hepatic microcirculation in cirrhosis: a study in the isolated perfused rat liver. Hepatology. 1989;9(6):820-3.
12. Bosch J, Abraldes JG, Groszmann R. Current management of portal hypertension. J Hepatol. 2003;38 Suppl 1:S54-68.
13. Gupta TK, Toruner M, Chung MK, et al. Endothelial dysfunction and decreased production of nitric oxide in the intrahepatic microcirculation of cirrhotic rats. Hepatology. 1998;28(4):926-31.
14. Rockey DC, Chung JJ. Reduced nitric oxide production by endothelial cells in cirrhotic rat liver: endothelial dysfunction in portal hypertension. Gastroenterology. 1998;114(2):344-51.
15. Shah V, Toruner M, Haddad F, et al. Impaired endothelial nitric oxide synthase activity associated with enhanced caveolin binding in experimental cirrhosis in the rat. Gastroenterology. 1999;117(5):1222-8.
16. Shah V, Cao S, Hendrickson H, et al. Regulation of hepatic eNOS by caveolin and calmodulin after bile duct ligation in rats. Am J Physiol Gastrointest Liver Physiol. 2001;280(6):G1209-16.
17. Bellis L, Berzigotti A, Abraldes JG, et al. Low doses of isosorbide mononitrate attenuate the postprandial increase in portal pressure in patients with cirrhosis. Hepatology. 2003;37(2):378-84.
18. Ceriello A, Taboga C, Tonutti L et al. Evidence for an independent and cumulative effect of postprandial hypertriglyceridemia and hyperglycemia on endothelial dysfunction and oxidative stress generation: effects of short- and long-term simvastatin treatment. Circulation. 2002;106(10):1211-8.
19. Van de Casteele M, Omasta A, Janssens S, et al. In vivo gene transfer of endothelial nitric oxide synthase decreases portal pressure in anaesthetised carbon tetrachloride cirrhotic rats. Gut. 2002;51(3):440-5.
20. Sarela AI, Mihaimeed FM, Batten JJ, et al. Hepatic and splanchnic nitric oxide activity in patients with cirrhosis. Gut. 1999;44(5):749-53.
21. Shah V. Cellular and molecular basis of portal hypertension. Clin Liver Dis. 2001 Aug;5(3):629-44.
22. Wiest R, Groszmann RJ. The paradox of nitric oxide in cirrhosis and portal hypertension: too much, not enough. Hepatology. 2002;35(2):478-91.
23. Liao JK. Inhibition of Gi proteins by low density lipoprotein attenuates bradykinin-stimulated release of endothelial-derived nitric oxide. J Biol Chem. 1994;269(17):12987-92.
24. Plenz GA, Hofnagel O, Robenek H. Differential modulation of caveolin-1 expression in cells of the vasculature by statins. Circulation. 2004;109(2):e7-8.
25. Dimmeler S, Fleming I, Fisslthaler B, et al. Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation. Nature. 1999;399 (6736):601-5.
26. Laufs U, Liao JK. Post-transcriptional regulation of endothelial nitric oxide synthase mRNA stability by Rho GTPase. J Biol Chem. 1998;273(37):24266-71.
27. Zafra C, Abraldes JG, Turnes J, et al. Simvastatin enhances hepatic nitric oxide production and decreases the hepatic vascular tone in patients with cirrhosis. Gastroenterology. 2004;126(3):749-55.
28. Abraldes JG, Albillos A, Bañares R, et al. Simvastatin lowers portal pressure in patients with cirrhosis and portal hypertension: a randomized controlled trial. Gastroenterology. 2009;136(5):1651-8.
29. Kamal S, Khan MA, Seth A, et al. Beneficial Effects of statins on the rates of hepatic fibrosis, hepatic decompensation, and mortality in chronic liver disease: A systematic review and meta-analysis. Am J Gastroenterol. 2017;112(10):1495-1505.
30. Boccuzzi SJ, Bocanegra TS, Walker JF, et al. Long-term safety and efficacy profile of simvastatin. Am J Cardiol. 1991;68(11):1127-31.
31. Collins R, Reith C, Emberson J, et al. Interpretation of the evidence for the efficacy and safety of statin therapy. Lancet. 2016;388(10059):2532-2561.
32. Abraldes JG, Villanueva C, Aracil C, et al. Addition of simvastatin to standard therapy for the prevention of variceal rebleeding does not reduce rebleeding but increases survival in patients with cirrhosis. Gastroenterology. 2016;150(5):1160-1170.e3.
33. Albarmawi A, Czock D, Gauss A, et al. CYP3A activity in severe liver cirrhosis correlates with Child-Pugh and model for end-stage liver disease (MELD) scores. Br J Clin Pharmacol. 2014;77(1):160-9.
34. Thompson PD, Panza G, Zaleski A, et al. Statin-associated side effects. J Am Coll Cardiol. 2016;67(20):2395-2410.
35. Pose E, Napoleone L, Amin A, et al. Safety of two different doses of simvastatin plus rifaximin in decompensated cirrhosis (LIVERHOPE-SAFETY): a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Gastroenterol Hepatol. 2020;(1):31-41.
36. Muñoz AE, Pollarsky F, Marino M, et al. Safety of chronic simvastatin treatment in patients with decompensated cirrhosis: Many adverse events but no liver injury. Dig Dis Sci. 2021;66(9):3199-3208.
37. Russo MW, Scobey M, Bonkovsky HL. Drug-induced liver injury associated with statins. Semin Liver Dis. 2009;29(4):412-22.
38. Muñoz AE, Pollarsky FD, Marino M, et al. Addition of statins to the standard treatment in patients with cirrhosis: Safety and efficacy. World J Gastroenterol. 2021;27(28):4639-4652.
39. Malizia G, D'Amico G. Statins in Cirrhosis: The magic pill? Hepatology. 2016;63(6):2047-9.
40. Muñoz AE, Pollarsky F, Marino M, et al. Baseline severity and Inflammation would influence the effect of simvastatin on clinical outcomes in cirrhosis patients. Dig Dis Sci. 2023;68(8):3442-3450.
41. Alvarado-Tapias E, Brujats A, Puente A, et al. Hemodynamic effects of carvedilol plus simvastatin in cirrhosis with severe portal hypertension and suboptimal response to β-blockers: A double-blind, placebo-controlled, randomized trial. Hepatology. 2025;82(1):140-154.
42. Tripathi DM, Vilaseca M, Lafoz E, et al. Simvastatin prevents progression of acute on chronic liver failure in rats with cirrhosis and portal hypertension. Gastroenterology. 2018;155(5):1564-1577.
43. Arroyo V, Moreau R, Jalan R. Acute-on-chronic liver failure. N Engl J Med. 2020;382(22):2137-2145.
44. Mahmud N, Chapin S, Goldberg DS, et al. Statin exposure is associated with reduced development of acute-on-chronic liver failure in a Veterans Affairs cohort. J Hepatol. 2022;76(5):1100-1108.
45. Chapin S, Kaplan DE, Taddei T, et al. Association between statin exposure and short-term mortality in patients with high-grade acute-on-chronic liver failure. JHEP Rep. 2023;5(6):100740.
46. Pose E, Jimenez C, Zaccherini G, et al. Simvastatin and rifaximin in decompensated cirrhosis: A randomized clinical trial. JAMA. 2025;333(10):864-874.
47. Deshpande A, Pasupuleti V, Rothberg MB. Statin therapy and mortality from sepsis: a meta-analysis of randomized trials. Am J Med. 2015;128(4):410-7.e1.
2. Devarbhavi H, Asrani SK, Arab JP, et al. Global burden of liver disease: 2023 update. J Hepatol. 2023;79(2):516-537.
3. Caraceni P, Abraldes JG, Gines P, et al. The search for disease-modifying agents in decompensated cirrhosis: From drug repurposing to drug discovery. J Hepatol. 2021;75 Suppl 1:S118-S134.
4. Verna EC, Morelli G, Terrault NA, et al. DAA therapy and long-term hepatic function in advanced/decompensated cirrhosis: Real-world experience from HCV-TARGET cohort. J Hepatol. 2020;73(3):540-548.
5. Adam R, Karam V, Cailliez V, et al. 2018 Annual Report of the European Liver Transplant Registry (ELTR) - 50-year evolution of liver transplantation. Transpl Int. 2018;(12):1293-1317.
6. Jadlowiec CC, Taner T. Liver transplantation: Current status and challenges. World J Gastroenterol. 2016;22(18):4438-45.
7. Morgan S, Grootendorst P, Lexchin J, et al. The cost of drug development: a systematic review. Health Policy. 2011;100(1):4-17.
8. Lai AG, Chang WH, Parisinos CA, et al. An informatics consult approach for generating clinical evidence for treatment decisions. BMC Med Inform Decis Mak. 2021;21(1):281.
9. Bosch J. Vascular deterioration in cirrhosis: the big picture. J Clin Gastroenterol. 2007;41 Suppl 3:S247-53.
10. Bhathal PS, Grossman HJ. Reduction of the increased portal vascular resistance of the isolated perfused cirrhotic rat liver by vasodilators. J Hepatol. 1985;1(4):325-37.
11. Marteau P, Ballet F, Chazouilleres O, et al. Effect of vasodilators on hepatic microcirculation in cirrhosis: a study in the isolated perfused rat liver. Hepatology. 1989;9(6):820-3.
12. Bosch J, Abraldes JG, Groszmann R. Current management of portal hypertension. J Hepatol. 2003;38 Suppl 1:S54-68.
13. Gupta TK, Toruner M, Chung MK, et al. Endothelial dysfunction and decreased production of nitric oxide in the intrahepatic microcirculation of cirrhotic rats. Hepatology. 1998;28(4):926-31.
14. Rockey DC, Chung JJ. Reduced nitric oxide production by endothelial cells in cirrhotic rat liver: endothelial dysfunction in portal hypertension. Gastroenterology. 1998;114(2):344-51.
15. Shah V, Toruner M, Haddad F, et al. Impaired endothelial nitric oxide synthase activity associated with enhanced caveolin binding in experimental cirrhosis in the rat. Gastroenterology. 1999;117(5):1222-8.
16. Shah V, Cao S, Hendrickson H, et al. Regulation of hepatic eNOS by caveolin and calmodulin after bile duct ligation in rats. Am J Physiol Gastrointest Liver Physiol. 2001;280(6):G1209-16.
17. Bellis L, Berzigotti A, Abraldes JG, et al. Low doses of isosorbide mononitrate attenuate the postprandial increase in portal pressure in patients with cirrhosis. Hepatology. 2003;37(2):378-84.
18. Ceriello A, Taboga C, Tonutti L et al. Evidence for an independent and cumulative effect of postprandial hypertriglyceridemia and hyperglycemia on endothelial dysfunction and oxidative stress generation: effects of short- and long-term simvastatin treatment. Circulation. 2002;106(10):1211-8.
19. Van de Casteele M, Omasta A, Janssens S, et al. In vivo gene transfer of endothelial nitric oxide synthase decreases portal pressure in anaesthetised carbon tetrachloride cirrhotic rats. Gut. 2002;51(3):440-5.
20. Sarela AI, Mihaimeed FM, Batten JJ, et al. Hepatic and splanchnic nitric oxide activity in patients with cirrhosis. Gut. 1999;44(5):749-53.
21. Shah V. Cellular and molecular basis of portal hypertension. Clin Liver Dis. 2001 Aug;5(3):629-44.
22. Wiest R, Groszmann RJ. The paradox of nitric oxide in cirrhosis and portal hypertension: too much, not enough. Hepatology. 2002;35(2):478-91.
23. Liao JK. Inhibition of Gi proteins by low density lipoprotein attenuates bradykinin-stimulated release of endothelial-derived nitric oxide. J Biol Chem. 1994;269(17):12987-92.
24. Plenz GA, Hofnagel O, Robenek H. Differential modulation of caveolin-1 expression in cells of the vasculature by statins. Circulation. 2004;109(2):e7-8.
25. Dimmeler S, Fleming I, Fisslthaler B, et al. Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation. Nature. 1999;399 (6736):601-5.
26. Laufs U, Liao JK. Post-transcriptional regulation of endothelial nitric oxide synthase mRNA stability by Rho GTPase. J Biol Chem. 1998;273(37):24266-71.
27. Zafra C, Abraldes JG, Turnes J, et al. Simvastatin enhances hepatic nitric oxide production and decreases the hepatic vascular tone in patients with cirrhosis. Gastroenterology. 2004;126(3):749-55.
28. Abraldes JG, Albillos A, Bañares R, et al. Simvastatin lowers portal pressure in patients with cirrhosis and portal hypertension: a randomized controlled trial. Gastroenterology. 2009;136(5):1651-8.
29. Kamal S, Khan MA, Seth A, et al. Beneficial Effects of statins on the rates of hepatic fibrosis, hepatic decompensation, and mortality in chronic liver disease: A systematic review and meta-analysis. Am J Gastroenterol. 2017;112(10):1495-1505.
30. Boccuzzi SJ, Bocanegra TS, Walker JF, et al. Long-term safety and efficacy profile of simvastatin. Am J Cardiol. 1991;68(11):1127-31.
31. Collins R, Reith C, Emberson J, et al. Interpretation of the evidence for the efficacy and safety of statin therapy. Lancet. 2016;388(10059):2532-2561.
32. Abraldes JG, Villanueva C, Aracil C, et al. Addition of simvastatin to standard therapy for the prevention of variceal rebleeding does not reduce rebleeding but increases survival in patients with cirrhosis. Gastroenterology. 2016;150(5):1160-1170.e3.
33. Albarmawi A, Czock D, Gauss A, et al. CYP3A activity in severe liver cirrhosis correlates with Child-Pugh and model for end-stage liver disease (MELD) scores. Br J Clin Pharmacol. 2014;77(1):160-9.
34. Thompson PD, Panza G, Zaleski A, et al. Statin-associated side effects. J Am Coll Cardiol. 2016;67(20):2395-2410.
35. Pose E, Napoleone L, Amin A, et al. Safety of two different doses of simvastatin plus rifaximin in decompensated cirrhosis (LIVERHOPE-SAFETY): a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Gastroenterol Hepatol. 2020;(1):31-41.
36. Muñoz AE, Pollarsky F, Marino M, et al. Safety of chronic simvastatin treatment in patients with decompensated cirrhosis: Many adverse events but no liver injury. Dig Dis Sci. 2021;66(9):3199-3208.
37. Russo MW, Scobey M, Bonkovsky HL. Drug-induced liver injury associated with statins. Semin Liver Dis. 2009;29(4):412-22.
38. Muñoz AE, Pollarsky FD, Marino M, et al. Addition of statins to the standard treatment in patients with cirrhosis: Safety and efficacy. World J Gastroenterol. 2021;27(28):4639-4652.
39. Malizia G, D'Amico G. Statins in Cirrhosis: The magic pill? Hepatology. 2016;63(6):2047-9.
40. Muñoz AE, Pollarsky F, Marino M, et al. Baseline severity and Inflammation would influence the effect of simvastatin on clinical outcomes in cirrhosis patients. Dig Dis Sci. 2023;68(8):3442-3450.
41. Alvarado-Tapias E, Brujats A, Puente A, et al. Hemodynamic effects of carvedilol plus simvastatin in cirrhosis with severe portal hypertension and suboptimal response to β-blockers: A double-blind, placebo-controlled, randomized trial. Hepatology. 2025;82(1):140-154.
42. Tripathi DM, Vilaseca M, Lafoz E, et al. Simvastatin prevents progression of acute on chronic liver failure in rats with cirrhosis and portal hypertension. Gastroenterology. 2018;155(5):1564-1577.
43. Arroyo V, Moreau R, Jalan R. Acute-on-chronic liver failure. N Engl J Med. 2020;382(22):2137-2145.
44. Mahmud N, Chapin S, Goldberg DS, et al. Statin exposure is associated with reduced development of acute-on-chronic liver failure in a Veterans Affairs cohort. J Hepatol. 2022;76(5):1100-1108.
45. Chapin S, Kaplan DE, Taddei T, et al. Association between statin exposure and short-term mortality in patients with high-grade acute-on-chronic liver failure. JHEP Rep. 2023;5(6):100740.
46. Pose E, Jimenez C, Zaccherini G, et al. Simvastatin and rifaximin in decompensated cirrhosis: A randomized clinical trial. JAMA. 2025;333(10):864-874.
47. Deshpande A, Pasupuleti V, Rothberg MB. Statin therapy and mortality from sepsis: a meta-analysis of randomized trials. Am J Med. 2015;128(4):410-7.e1.