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Myopathy with statin–fibrate combination therapy: clinical considerations

Nature Reviews Endocrinology volume 5, pages 507–518 (2009)Cite this article

Abstract

Many patients who receive statin therapy for hyperlipidemia—such as patients with diabetes mellitus and metabolic syndrome—have residual cardiovascular risk. These patients often have dyslipidemia, including low levels of HDL cholesterol and elevated levels of triglycerides and small, dense LDL. For such patients, combination treatment with statins and fibrates is a potentially useful strategy to improve lipid and lipoprotein profiles and reduce cardiovascular risk. However, statin–fibrate combination regimens have potential adverse effects on skeletal muscle, including myopathy. To date, no large-scale, prospective, randomized, controlled trial has evaluated the safety and efficacy of statin–fibrate combination therapy; one such trial is underway but will not report data until 2010. Until then, clinicians need to consider pharmacokinetic, pharmacodynamic, metabolic, pathophysiologic and other factors that can increase the systemic exposure of statins and/or fibrates and hence heighten the risk of toxic effects on muscles, as well as data from clinical trials and recommendations of consensus panels to optimize the safety of such combination regimens. On the basis of currently available data, fenofibrate or fenofibric acid is the fibrate of choice when used in combination with a statin because each is, in theory, associated with a lower risk of myopathy than gemfibrozil.

Key Points

  • Statin–fibrate combination regimens might be useful for patients with insulin resistance and certain types of dyslipidemia; however, the safety and efficacy of such therapy have not been systematically evaluated

  • Risk factors of statin–fibrate-related myopathy include advanced age, female gender, low BMI, renal disease, diabetes mellitus, hypothyroidism, multisystem disease, fever, surgery, trauma, and strenuous physical exercise

  • The likelihood and/or severity of myopathy also depend on pharmacologic properties of the statin and the fibrate, such as their enzymatic metabolism or excretion and/or their protein-regulated intercellular transport

  • Fenofibrate or fenofibric acid may be fibrates of choice for statin–fibrate therapy because, according to pharmacokinetic and postmarketing data, they are associated with lower risks of myopathy (versus gemfibrozil)

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Figure 1: Concepts in the pathogenesis of myopathy associated with lipid-modifying therapies.
Figure 2: Changes in geometric mean plasma concentrations of a | rosuvastatin after dosing of rosuvastatin alone and rosuvastatin in combination with fenofibrate; and b | fenofibrate after dosing of fenofibrate alone and in combination with rosuvastatin.
Figure 3: Number of cases of rhabdomyolysis reported per million prescriptions dispensed of a | cerivastatin in combination with fenofibrate or gemfibrozil and b | statins other than cerivastatin in combination with fenofibrate or gemfibrozil.

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Acknowledgements

Editorial assistance was provided by Stephen W. Gutkin, Rete Biomedical Communications Corp. (Wyckoff, NJ, USA).

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  1. Department of Medicine, Office of Health Promotion and Disease Prevention, Emory University School of Medicine, Atlanta, GA, USA

    Terry A. Jacobson

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Correspondence to Terry A. Jacobson.

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The author declares associations with the following companies: Abbott (consultant), AstraZeneca (consultant), Merck (consultant), GlaxoSmithKline (consultant), and Schering-Plough (consultant).

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Supplementary Box 1

Summary of manufacturers' recommendations when prescribing statins together with fibrates (and fibrates with statins) (DOC 51 kb)

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Jacobson, T. Myopathy with statin–fibrate combination therapy: clinical considerations. Nat Rev Endocrinol 5, 507–518 (2009). https://doi.org/10.1038/nrendo.2009.151

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