Reporting rate of rhabdomyolysis with fenofibrate + statin versus gemfibrozil + any statin

doi:10.1016/j.amjcard.2004.08.076

The American Journal of Cardiology

Volume 95, Issue 1, 1 January 2005, Pages 120-122

https://doi.org/10.1016/j.amjcard.2004.08.076 Get rights and content

There is an increasing trend among physicians to use 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) in combination with other antilipidemic agents. The complementary lipid-altering effects of statins and fibric acid derivatives (fibrates) have led to an increasing use of statin/fibrate combination therapy, particularly for patients who have mixed dyslipidemia. Clinical experience indicates that there may be an increased risk of myotoxicity associated with statin/fibrate combination therapy. However, it is not known whether there are differences in the rate of myotoxicity between the use of fenofibrate and gemfibrozil in combination with statins. To evaluate this question, data from the United States Food and Drug Administration's Adverse Event Reporting System was reviewed to determine how many adverse events were reported for patients who were being treated concomitantly with statins and fibrates. The findings suggest that the use of fenofibrate in combination with statins results in fewer reports of rhabdomyolysis per million prescriptions dispensed than does the use of gemfibrozil.

References (18)

M.H. Davidson et al.
The efficacy and six-week tolerability of simvastatin 80 and 160 mg/day
Am J Cardiol
(1997)
T. Prueksaritanont et al.
Effects of fibrates on metabolism of statins in human hepatocytes
Drug Metab Dispos
(2002)
T. Prueksaritanont et al.
Mechanistic studies on metabolic interactions between gemfibrozil and statins
J Pharmacol Exp Ther
(2002)
J.S. Wang et al.
Gemfibrozil inhibits CYP2C8-mediated cerivastatin metabolism in human liver microsomes
Drug Metab Dispos
(2002)
M. Niemi et al.
Effects of gemfibrozil, itraconazole, and their combination on the pharmacokinetics and pharmacodynamics of repaglinide: potentially hazardous interaction between gemfibrozil and repaglinide
Diabetologia
(2003)
M. Niemi et al.
Gemfibrozil considerably increases the plasma concentrations of rosiglitazone
Diabetologia
(2003)
T.B. Bidstrup et al.
CYP2C8 and CYP3A4 are the principal enzymes involved in the human in vitro biotransformation of the insulin secretagogue repaglinide
Br J Clin Pharmacol
(2003)
S.J. Baldwin et al.
Characterization of the cytochrome P450 enzymes involved in the in vitro metabolism of rosiglitazone
Br J Clin Pharmacol
(1999)
C. Kyrklund et al.
Gemfibrozil increases plasma pravastatin concentrations and reduces pravastatin renal clearance
Clin Pharmacol Ther
(2003)

There are more references available in the full text version of this article.

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Citation Excerpt :
The combination of gemfibrozil and repaglinide is contraindicated because of the risk of severe hypoglycemia. In comparison to gemfibrozil, the use of fenofibrate with a statin carries a much lower risk of myopathy/rhabdomyolysis.82,83 Fenofibrate may increase LFTs (3%–7% of patients) and plasma creatinine (see Table 4).
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: This study was supported by a grant from Abbott Laboratories, North Chicago, Illinois.

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Brief reportsReporting rate of rhabdomyolysis with fenofibrate + statin versus gemfibrozil + any statin

Am J Cardiol

Effects of fibrates on metabolism of statins in human hepatocytes

Drug Metab Dispos

Mechanistic studies on metabolic interactions between gemfibrozil and statins

J Pharmacol Exp Ther

Gemfibrozil inhibits CYP2C8-mediated cerivastatin metabolism in human liver microsomes

Drug Metab Dispos

Effects of gemfibrozil, itraconazole, and their combination on the pharmacokinetics and pharmacodynamics of repaglinide: potentially hazardous interaction between gemfibrozil and repaglinide

Diabetologia

Gemfibrozil considerably increases the plasma concentrations of rosiglitazone

Diabetologia

CYP2C8 and CYP3A4 are the principal enzymes involved in the human in vitro biotransformation of the insulin secretagogue repaglinide

Br J Clin Pharmacol

Characterization of the cytochrome P450 enzymes involved in the in vitro metabolism of rosiglitazone

Br J Clin Pharmacol

Gemfibrozil increases plasma pravastatin concentrations and reduces pravastatin renal clearance

Clin Pharmacol Ther

Brief reports
Reporting rate of rhabdomyolysis with fenofibrate + statin versus gemfibrozil + any statin