Skip to main content

Advertisement

SpringerLink
Log in

Gemfibrozil in Combination with Statins—Is It Really Contraindicated?

  • Statin Drugs (B. Wiggins, Section Editor)
  • Published:
Current Atherosclerosis Reports Aims and scope Submit manuscript

Abstract

Gemfibrozil is a lipid-modifying agent that belongs to the fibric acid derivative class. Fibric acid derivatives activate peroxisome proliferator activated receptor α (PPAR-α). The primary role of these agents in clinical practice is for the management of hypertriglyceridemia. Triglycerides may be reduced by as much as 74 % in some patients. In addition to lowering triglycerides, these agents can also decrease very low-density lipoprotein cholesterol (VLDL-C) and low-density lipoprotein cholesterol (LDL-C) as well as raise high-density lipoprotein cholesterol (HDL-C). Based on the 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults and the National Lipid Association, pharmacologic therapy to reduce triglycerides should be considered when triglyceride levels are ≥500 mg/dL. While the use of gemfibrozil has decreased over the years for a variety of reasons, muscle-associated adverse effects is the predominant reason and the one that is most clinically relevant. However, despite these concerns, there are situations in which the use of gemfibrozil in combination with a statin may be necessary. Understanding the metabolism of gemfibrozil and the degree of interaction with the various statins will assist health-care providers to optimize safety when this combination is clinically indicated.

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

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129:S1–45.

    Article  PubMed  Google Scholar 

  2. Jacobson TA, Ito MK, Maki KC, et al. National Lipid Association recommendations for patient-centered management of dyslipidemia: part 1—executive summary. J Clin Lipidol. 2014;8:473–88.

    Article  PubMed  Google Scholar 

  3. Sher T, Yi HF, McBride OW, Gonzalez FJ. cDNA cloning, chromosomal mapping, and functional characterization of the human peroxisome proliferator activated receptor. Biochemistry. 1993;32:5598–604.

    Article  CAS  PubMed  Google Scholar 

  4. Staels B, Dallongeville J, Auwerx J, Schoonjans K, Leitersdorf E, Fruchart JC. Mechanism of action of fibrates on lipid and lipoprotein metabolism. Circulation. 1998;98:2088–93.

    Article  CAS  PubMed  Google Scholar 

  5. Packard CJ. Overview of fenofibrate. Eur Heart J. 1998;19(Suppl A):A62–5.

    CAS  PubMed  Google Scholar 

  6. Bard JM, Parra HJ, Camare R, et al. A multicenter comparison of the effects of simvastatin and fenofibrate therapy in severe primary hypercholesterolemia, with particular emphasis on lipoproteins defined by their apolipoprotein composition. Metab Clin Exp. 1992;41:498–503.

    Article  CAS  PubMed  Google Scholar 

  7. Lussier-Cacan S, Bard JM, Boulet L, et al. Lipoprotein composition changes induced by fenofibrate in dysbetalipoproteinemia type III. Atherosclerosis. 1989;78:167–82.

    Article  CAS  PubMed  Google Scholar 

  8. Leaf DA, Connor WE, Illingworth DR, Bacon SP, Sexton G. The hypolipidemic effects of gemfibrozil in type V hyperlipidemia. A double-blind, crossover study. JAMA. 1989;262:3154–60.

    Article  CAS  PubMed  Google Scholar 

  9. Frick MH, Elo O, Haapa K, et al. Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease. N Engl J Med. 1987;317:1237–45.

    Article  CAS  PubMed  Google Scholar 

  10. Rubins HB, Robins SJ, Collins D, et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. N Engl J Med. 1999;341:410–8.

    Article  CAS  PubMed  Google Scholar 

  11. Rubins HB, Robins SJ, Collins D, et al. Diabetes, plasma insulin, and cardiovascular disease: subgroup analysis from the Department of Veterans Affairs High-Density Lipoprotein Intervention Trial (VA-HIT). Arch Intern Med. 2002;162:2597–604.

    Article  CAS  PubMed  Google Scholar 

  12. Henry K, Melroe H, Huebesch J, et al. Atorvastatin and gemfibrozil for protease-inhibitor-related lipid abnormalities. Lancet. 1998;52:1031–2.

    Article  Google Scholar 

  13. Jacobson TA. NLA Task Force on Statin Safety—2014 update. J Clin Lipidol. 2014;8:S1–4.

    Article  Google Scholar 

  14. Omar MA, Wilson JP. FDA adverse event reports on statin-associated rhabdomyolysis. Ann Pharmacother. 2002;36:288–95.

    Article  CAS  PubMed  Google Scholar 

  15. Rosenson RS, Baker SK, Jacobson TA, Kopecky SL, Parker BA. An assessment by the Statin Muscle Safety Task Force: 2014 update. J Clin Lipidol. 2014;8:S58–71.

    Article  PubMed  Google Scholar 

  16. Chang JT, Staffa JA, Parks M, Green L. Rhabdomyolysis with HMG-CoA reductase inhibitors and gemfibrozil combination therapy. Pharmacoepidemiol Drug Saf. 2004;13:417–26.

    Article  CAS  PubMed  Google Scholar 

  17. Jones PH, Davidson MH. Reporting rate of rhabdomyolysis with fenofibrate + statin versus gemfibrozil + any statin. Am J Cardiol. 2005;95:120–2. This was a search of the FDA adverse event report system to evaluate if the incidence of myotoxicity association with the statin/fibrate combination is greater with the combination of gemfibrozil/statin or fenofibrate/statin. There were fewer reports of rhabdomyolysis with fenofibrate than with gemfibrozil when used in combination with a statin.

  18. Andrade SE, Graham DJ, Staffa JA, et al. Health plan administrative databases can efficiently identify serious myopathy and rhabdomyolysis. J Clin Epidemiol. 2005;58:171–4.

    Article  PubMed  Google Scholar 

  19. Cziraky MJ, Willey VJ, McKenney JM, et al. Statin safety: an assessment using an administrative claims database. Am J Cardiol. 2006;97:61C–8.

    Article  CAS  PubMed  Google Scholar 

  20. Graham DJ, Staffa JA, Shatin D, et al. Incidence of hospitalized rhabdomyolysis in patients treated with lipid-lowering drugs. JAMA. 2004;292:2585–90.

    Article  CAS  PubMed  Google Scholar 

  21. Pasternak RC, Smith Jr SC, Bairey-Merz CN, Grundy SM, Cleeman JI, Lenfant C. ACC/AHA/NHLBI clinical advisory on the use and safety of statins. J Am Coll Cardiol. 2002;40:567–72.

    Article  PubMed  Google Scholar 

  22. Alford JC, Saseen JJ, Allen RR, Nair KV. Persistent use of against-label statin-fibrate combinations from 2003–2009 despite United States Food and Drug Administration dose restrictions. Pharmacotherapy. 2012;32:623–30.

    Article  CAS  PubMed  Google Scholar 

  23. U.S. Food and Drug Administration. FDA drug safety communication: new restrictions, contraindications, and dose limitations for Zocor (simvastatin) to reduce the risk of muscle injury. Published 6/8/11, Available at: http://www.fda.gov/Drugs/DrugSafety/ucm256581.htm.

  24. Gemfibrozil (Lopid) prescribing information. New York, NY: Parke-Davis; 2012.

  25. VandenBrink BM, Isoherranen N. The role of metabolites in predicting drug-drug interactions: focus on irreversible cytochrome P450 inhibition. Curr Opin Drug Discov Dev. 2010;13:66–77.

    CAS  Google Scholar 

  26. Bellosta S, Paoletti R, Corsini A. Safety of statins: focus on clinical pharmacokinetics and drug interactions. Circulation. 2004;109:III50–7.

    Article  PubMed  Google Scholar 

  27. Kalliokoski A, Niemi M. Impact of OATP transporters on pharmacokinetics. Br J Pharmacol. 2009;158:693–705.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Shitara Y, Hirano M, Sato H, Sugiyama Y. Gemfibrozil and its glucuronide inhibit the organic anion transporting polypeptide 2 (OATP2/OATP1B1:SLC21A6)-mediated hepatic uptake and CYP2C8-mediated metabolism of cerivastatin: analysis of the mechanism of the clinically relevant drug-drug interaction between cerivastatin and gemfibrozil. J Pharmacol Exp Ther. 2004;311:228–36.

    Article  CAS  PubMed  Google Scholar 

  29. Prueksaritanont T, Tang C, Qiu Y, Mu L, Subramanian R, Lin JH. Effects of fibrates on metabolism of statins in human hepatocytes. Drug Metab Dispos: Biol Fate Chem. 2002;30:1280–7.

    Article  CAS  Google Scholar 

  30. Prueksaritanont T, Zhao JJ, Ma B, et al. Mechanistic studies on metabolic interactions between gemfibrozil and statins. J Pharmacol Exp Ther. 2002;301:1042–51.

    Article  CAS  PubMed  Google Scholar 

  31. Backman JT, Kyrklund C, Kivisto KT, Wang JS, Neuvonen PJ. Plasma concentrations of active simvastatin acid are increased by gemfibrozil. Clin Pharmacol Ther. 2000;68:122–9.

    Article  CAS  PubMed  Google Scholar 

  32. Kyrklund C, Backman JT, Kivisto KT, Neuvonen M, Laitila J, Neuvonen PJ. Plasma concentrations of active lovastatin acid are markedly increased by gemfibrozil but not by bezafibrate. Clin Pharmacol Ther. 2001;69:340–5.

    Article  CAS  PubMed  Google Scholar 

  33. Whitfield LR, Porcari AR, Alvey C, Abel R, Bullen W, Hartman D. Effect of gemfibrozil and fenofibrate on the pharmacokinetics of atorvastatin. J Clin Pharmacol. 2011;51:378–88.

    Article  CAS  PubMed  Google Scholar 

  34. Backman JT, Luurila H, Neuvonen M, Neuvonen PJ. Rifampin markedly decreases and gemfibrozil increases the plasma concentrations of atorvastatin and its metabolites. Clin Pharmacol Ther. 2005;78:154–67.

    Article  CAS  PubMed  Google Scholar 

  35. Kyrklund C, Backman JT, Neuvonen M, Neuvonen PJ. Gemfibrozil increases plasma pravastatin concentrations and reduces pravastatin renal clearance. Clin Pharmacol Ther. 2003;73:538–44. This was a randomized placebo-controlled, 2-phase crossover study to evaluate the effects of gemfibrozil on the pharmacokinetics of pravastatin. The results showed an increase in the plasma concentration of pravastatin when combined with gemfiborzil. The increase is in part related to a reduction in renal clearance of pravastatin.

  36. Bergman E, Matsson EM, Hedeland M, Bondesson U, Knutson L, Lennernas H. Effect of a single gemfibrozil dose on the pharmacokinetics of rosuvastatin in bile and plasma in healthy volunteers. J Clin Pharmacol. 2010;50:1039–49. This study evaluated the plasma pharmacokinetics and biliary excretion effects of gemfibrozil on rosuvastatin. Bile and plasma levels were obtained every 20 minutes following administration for 200 minutes. The results showed that gemfibrozil increased the area under the curve by 1.56 fold, indicating that the interaction is minor and perhaps the combination can be used.

  37. Schneck DW, Birmingham BK, Zalikowski JA, et al. The effect of gemfibrozil on the pharmacokinetics of rosuvastatin. Clin Pharmacol Ther. 2004;75:455–63. This was a randomized, double-blind trial, 2 period cross over trial evaluating the effects of gemfibrozil on the plasma concentration of rosuvastatin and its metabolites. The results showed that the area under the curve of rosuvastatin was increased by approximately 2 fold. The mechanism may be secondary to the inhibition of OATP2-mediated rosuvastatin hepatic uptake by gemfibrozil.

  38. Noe J, Portmann R, Brun ME, Funk C. Substrate-dependent drug-drug interactions between gemfibrozil, fluvastatin and other organic anion-transporting peptide (OATP) substrates on OATP1B1, OATP2B1, and OATP1B3. Drug Metab Dispos: Biol Fate Chem. 2007;35:1308–14.

    Article  CAS  Google Scholar 

  39. Spence JD, Munoz CE, Hendricks L, Latchinian L, Khouri HE. Pharmacokinetics of the combination of fluvastatin and gemfibrozil. Am J Cardiol. 1995;76:80A–3. This was an open-label, crossover study evaluating the impact of gemfibrozil on the pharmacokinetics of fluvastatin. The results showed no significant impact on area under the curve, time to maximum concentration, or maximum plasma concentration when fluvastatin is combined with gemfibrozil.

  40. Reiner Z, Catapano AL, De Backer G, et al. ESC/EAS guidelines for the management of dyslipidaemias: the Task Force for the Management of Dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J. 2011;32:1769–818.

    Article  PubMed  Google Scholar 

  41. Atorvastatin (Lipitor) prescribing information. New York, NY: Pfizer; 2013.

  42. Fluvastatin sodium (Lescol, Lescol XL) prescribing information. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2012.

  43. Lovastatin (Mevacor) prescribing information. Whitehouse Station, NJ: Merck & Co., INC; 2014.

  44. Pravastatin (Pravachol) prescribing information. Princeton, NJ: Bristol-Myers Squibb; 2013.

  45. Rosuvastatin (Crestor) prescribing information. Wilmington, DE: AztraZeneca Pharmaceuticals; 2013.

  46. Simvastatin (Zocor) prescribing information. Whitehouse Station, NJ: Merck & Co., INC; 2014.

  47. Pitavastatin (Livalo) prescribing information. Montgomery, AL: Kowa Pharmaceuticals; 2013.

  48. Tuchscherer RM, Nair K, Ghushchyan V, Saseen JJ. Simvastatin prescribing patterns before and after FDA dosing restrictions: a retrospective analysis of a large healthcare claims database. Am J Cardiovasc Drugs : Drugs Devices Other Interv. 2015;15:27–34. These references provide detail the effects of specific statins and their interaction with gemfibrozil. Given the differences in metabolism of statins the clinical impact of coadministration with gemfibrozil varies. Understanding these differences will assist with clinical decision making.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmacy Services, Medical University of South Carolina, 25 Courtenay Drive, MSC 584, Charleston, SC, USA

    Barbara S. Wiggins

  2. Skaggs School of Pharmacy and Pharmaceutical Sciences, Department of Clinical Pharmacy, University of Colorado Anschutz Medical Campus, Aurora, CO, USA

    Joseph J. Saseen

  3. School of Medicine, Department of Family Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA

    Joseph J. Saseen

  4. School of Medicine, Department of Medicine Charleston, Medical University of South Carolina, Charleston, SC, USA

    Pamela B. Morris

Authors
  1. Barbara S. Wiggins
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Joseph J. Saseen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Pamela B. Morris
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Barbara S. Wiggins.

Ethics declarations

Conflict of Interest

Barbara S. Wiggins and Joseph J. Saseen declare that they have no conflict of interest.

Pamela B. Morris declares serving on the advisory board for Amgen, AstraZeneca, and Sanofi Regeneron.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

This article is part of the Topical Collection on Statin Drugs

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wiggins, B.S., Saseen, J.J. & Morris, P.B. Gemfibrozil in Combination with Statins—Is It Really Contraindicated?. Curr Atheroscler Rep 18, 18 (2016). https://doi.org/10.1007/s11883-016-0571-8

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11883-016-0571-8

Keywords

Search

Navigation