Skip to main content
SpringerLink
Log in

Hepatic Effects of Lovastatin Exposure in Patients with Liver Disease

A Retrospective Cohort Study

  • Original Research Article
  • Published:
Drug Safety Aims and scope Submit manuscript

Abstract

Background: Little is known about the potential adverse hepatic effects of HMG-CoA reductase inhibitors (‘statins’) in patients with existing liver disease; therefore, we examined the risk of liver toxicity with lovastatin exposure in these patients.

Methods: A retrospective cohort study was performed using data from a large integrated health plan in Northern California, USA. Patients with laboratory or clinical evidence of liver disease were identified and their exposure to lovastatin was determined. The primary outcome was a pattern of liver-test abnormalities associated with a poor prognosis among patients with drug-induced liver disease, based on Hy’s Rule. Secondary outcomes included liver injury (defined as moderate or severe, depending on the degree of ALT level elevations) or the development of either clinical cirrhosis or liver failure. Incidence rate ratios (IRRs) were calculated and multivariate analyses conducted using extended Cox models.

Results: A total of 93 106 patients met the entry criteria. Lovastatin exposure was associated with a lower incidence of all endpoints, including the primary outcome (IRR = 0.28, 95% CI 0.12, 0.55), moderate liver injury (IRR = 0.56, 95% CI 0.47, 0.65), severe liver injury (IRR = 0.50, 95% CI 0.29, 0.81) and the occurrence of either cirrhosis or liver failure (IRR = 0.29, 95% CI 0.21, 0.38); adjustment for age and sex resulted in some attenuation of this reduction in incidence. The observed effects were generally consistent across a range of baseline liver-disease diagnoses and greater cumulative lovastatin exposure was associated with fewer outcome events for some endpoints.

Conclusions: In this retrospective analysis, exposure to lovastatin was not associated with an increased risk of adverse hepatic outcomes. These results do not support concern regarding lovastatin-related hepatotoxicity in patients with existing liver disease.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Table I
Table II
Table III
Table IV
Table V
Fig. 1
Table VI

Similar content being viewed by others

References

  1. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994 Nov 19; 344(8934): 1383–9

    Google Scholar 

  2. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002 Jul 6; 360(9326): 7–22

    Article  Google Scholar 

  3. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. N Engl J Med 1998 Nov 5; 339(19): 1349–57

    Article  Google Scholar 

  4. Downs JR, Clearfield M, Weis S, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA 1998 May 27; 279(20): 1615–22

    Article  PubMed  CAS  Google Scholar 

  5. Sacks FM, Pfeffer MA, Moye LA, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. N Engl J Med 1996 Oct 3; 335(14): 1001–9

    Article  PubMed  CAS  Google Scholar 

  6. Shepherd J, Cobbe SM, Ford I, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N Engl J Med 1995 Nov 16; 333(20): 1301–7

    Article  PubMed  CAS  Google Scholar 

  7. Pasternak RC, Smith Jr SC, Bairey-Merz CN, et al. ACC/AHA/ NHLBI clinical advisory on the use and safety of statins. Circulation 2002 Aug 20; 106(8): 1024–8

    Article  PubMed  Google Scholar 

  8. Caldwell SH, Zaidman JS, Hespenheide EE. The liver and statin drug therapy: uncertain navigation in the sea of risk-benefit. Pharmacoepidemiol Drug Saf 2003 Jun; 12(4): 303–6

    Article  PubMed  Google Scholar 

  9. de Denus S, Spinler SA, Miller K, et al. Statins and liver toxicity: a meta-analysis. Pharmacotherapy 2004 May; 24(5): 584–91

    Article  PubMed  Google Scholar 

  10. Pfeffer MA, Keech A, Sacks FM, et al. Safety and tolerability of pravastatin in long-term clinical trials: Prospective Pravastatin Pooling (PPP) Project. Circulation 2002 May 21; 105(20): 2341–6

    Article  PubMed  CAS  Google Scholar 

  11. Charles EC, Olson KL, Sandhoff BG, et al. Evaluation of cases of severe statin-related transaminitis within a large health maintenance organization. Am J Med 2005 Jun; 118(6): 618–24

    Article  PubMed  CAS  Google Scholar 

  12. Tolman KG. The liver and lovastatin. Am J Cardiol 2002 Jun 15; 89(12): 1374–80

    Article  PubMed  CAS  Google Scholar 

  13. Bradford RH, Shear CL, Chremos AN, et al. Expanded Clinical Evaluation of Lovastatin (EXCEL) study results: I. Efficacy in modifying plasma lipoproteins and adverse event profile in 8245 patients with moderate hypercholesterolemia. Arch Intern Med 1991 Jan; 151(1): 43–9

    Article  PubMed  CAS  Google Scholar 

  14. McKenney JM, Davidson MH, Jacobson TA, et al. Final conclusions and recommendations of the national lipid association statin safety assessment task force. Am J Cardiol 2006 Apr 17; 97(8A): S89–94

    Article  Google Scholar 

  15. Anfossi G, Massucco P, Bonomo K, et al. Prescription of statins to dyslipidemic patients affected by liver diseases: a subtle balance between risks and benefits. Nutr Metab Cardiovasc Dis 2004 Aug; 14(4): 215–24

    Article  PubMed  CAS  Google Scholar 

  16. Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001 May 16; 285(19): 2486–97 334

    Article  Google Scholar 

  17. Zimmerman HJ. Hepatotoxicity: adverse effects of drugs and other chemicals on the liver. New York: Appleton-Century-Crofts, 1978

    Google Scholar 

  18. Andrade RJ, Lucena MI, Fernandez MC, et al. Drug-induced liver injury: an analysis of 461 incidences submitted to the Spanish registry over a 10-yearperiod. Gastroenterology 2005; 129: 512–21

    PubMed  Google Scholar 

  19. Bjornsson E. Drug-induced liver injury: Hy’s rule revisited. Clin Pharmcol Ther 2006; 79: 521–8

    Article  Google Scholar 

  20. Bjornsson E, Olsson R. Outcome and prognostic markers in severe drug-induced liver disease. Hepatology 2005 Aug; 42(2): 481–9

    Article  PubMed  Google Scholar 

  21. Rothman KJ. Modern epidemiology. 2nd ed. Philadelphia (PA): Lippincott-Raven, 1998

    Google Scholar 

  22. Stata Corporation. Stata Statistical Software, telease 9. College Station (TX): Stata Corporation, 2005

    Google Scholar 

  23. Kleinbaum DG, Klein M. Survival analysis. 2nd ed. New York: Springer, 2005

    Google Scholar 

  24. Snedecor GW, Cochrane WG. Statistical methods. Ames (IA): The Iowa State University Press, 1980

    Google Scholar 

  25. Cupp MJ, Tracy TS. Cytochrome P450: new nomenclature and clinical implications. Am Fam Physician 1998 Jan 1; 57(1): 107–16

    PubMed  CAS  Google Scholar 

  26. Feenstra H, Grobbee RE, in’t Veld BA, et al. Confounding by contraindication in a nationwide cohort study of risk for death in patients taking ibopamine. Ann Intern Med 2001 Apr 3; 134(7): 569–72

    PubMed  CAS  Google Scholar 

  27. Diggle PJ, Haegerty P, Liang K-Y, et al. Analysis of longitudinal data. 2nd ed. Oxford: Oxford University Press, 2002

    Google Scholar 

  28. Benner JS, Glynn RJ, Mogun H, et al. Long-term persistence in use of statin therapy in elderly patients. JAMA 2002 Jul 24–31; 288(4): 455–61

    Article  PubMed  Google Scholar 

  29. Ellis JJ, Erickson SR, Stevenson JG, et al. Suboptimal statin adherence and discontinuation in primary and secondary prevention populations. J Gen Intern Med 2004 Jun; 19(6): 638–45

    Article  PubMed  Google Scholar 

  30. Jackevicius CA, Mamdani M, Tu JV. Adherence with statin therapy in elderly patients with and without acute coronary syndromes. JAMA 2002 Jul 24–31; 288(4): 462–7

    Article  PubMed  Google Scholar 

  31. Chalasani N, Aljadhey H, Kesterson J, et al. Patients with elevated liver enzymes are not at higher risk for statin hepatotoxicity. Gastroenterology 2004 May; 126(5): 1287–92

    Article  PubMed  CAS  Google Scholar 

  32. Vuppalanchi R, Teal E, Chalasani N. Patients with elevated baseline liver enzymes do not have higher frequency of hepatotoxicity from lovastatin than those with normal baseline liver enzymes. Am J Med Sci 2005 Feb; 329(2): 62–5

    Article  PubMed  Google Scholar 

  33. Lewis JH, Zweig SF, Belder R. Is the lipid reduction seen with high-dose pravastatin (PRAVA) associated with a fall in ALT values in hypercholesterolemic pts with NAFLD? Results from a prospective, randomized double-blind, placebo (PBO)-controlled trial abstract no. 346]. Am J Gastroenterol 2006; 101: S158

    Google Scholar 

  34. Cohen DE, Anania FA, Chalasani N. An assessment of statin safety by hepatologists. Am J Cardiol 2006 Apr 17; 97(8S1): S77–81

    Article  Google Scholar 

  35. Rallidis LS, Drakoulis CK, Parasi AS. Pravastatin in patients with non-alcoholic steatohepatitis: results of a pilot study. Atherosclerosis 2004; 174: 193–6

    Article  PubMed  CAS  Google Scholar 

  36. Kiyici M, Gulten M, Gurel S, et al. Ursodeoxycholic acid and atorvastatin in the treatment of non-alcoholic steatohepatitis. Can J Gastroenterol 2003 Dec; 17(12): 713–8

    PubMed  Google Scholar 

  37. Horlander J, Kwo P, Cummings O, et al. Atorvastatin for the treatment of NASH abstract]. Gastroenterology 2001; 120: A544

    Google Scholar 

Download references

Acknowledgements

Funding for this study was provided by Merck & Co., West Point, Pennsylvania, USA.

Drs Avins, Manos, Ackerson, Murphy and Levin have received research support and Dr Zhao has received salary support for this study from Merck & Co. Dr Watson, Dr Hwang, Ms Replogle and Dr Levine are employees of Merck & Co.

Author information

Authors and Affiliations

  1. Kaiser Permanente Division of Research, 2000 Broadway, 3rd Floor, Oakland, California, 94612, USA

    Andrew L. Avins, Michele M. Manos, Lynn Ackerson, Wei Zhao, Rosemary Murphy & Theodore R. Levin

  2. Department of Medicine, University of California, San Francisco, USA

    Andrew L. Avins

  3. Department of Epidemiology & Biostatistics, University of California, San Francisco, USA

    Andrew L. Avins & Michele M. Manos

  4. Veterans Affairs Medical Center, San Francisco, California, USA

    Andrew L. Avins

  5. Merck & Co., West Point, Pennsylvania, USA

    Douglas J. Watson, Peggy M. T. Hwang, Amy Replogle & Jeffrey G. Levine

Authors
  1. Andrew L. Avins
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michele M. Manos
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lynn Ackerson
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Wei Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Rosemary Murphy
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Theodore R. Levin
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Douglas J. Watson
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Peggy M. T. Hwang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Amy Replogle
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Jeffrey G. Levine
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Andrew L. Avins.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Avins, A.L., Manos, M.M., Ackerson, L. et al. Hepatic Effects of Lovastatin Exposure in Patients with Liver Disease. Drug-Safety 31, 325–334 (2008). https://doi.org/10.2165/00002018-200831040-00006

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00002018-200831040-00006

Keywords

Search

Navigation