Simvastatin, Fenofibrate, and Rhabdomyolysis

The National Cholesterol Education Program (NCEP) guidelines recommend use of statin-fibrate combinations to treat combined dyslipidemia. Myopathy and rhabdomyolysis are reported side effects, especially with gemfibrozil-statin combinations (1). This risk is recognized to result from both pharmacodynamic and pharmacokinetic interactions. In vitro studies in human hepatocytes have shown that unlike gemfibrozil, fenofibrate has no pharmacokinetic interaction with simvastatin at concentrations achieved with clinical dosing (2). The acid form of simvastatin is partly eliminated by glucuronidation and lactonization, both of which are inhibited by gemfibrozil but not fenofibrate (2). This lack of a pharmacokinetic interaction between simvastatin and fenofibrate relaxed the recommendation in the package insert for simvastatin, allowing all doses to be used in combination with fenofibrate. A recent NCEP guideline update also supports lessening concern regarding this combination (3). Hence, it is frequently prescribed for combined dyslipidemia. We report a case of rhabdomyolysis with this combination that raises questions regarding its safety and suggests that caution is still in order.

A 70-year-old man with a history of type 2 diabetes, dyslipidemia, hypertension, and hypothyroidism presented with 2 weeks of bilateral leg myalgia. Four weeks before presentation, he was started on 160 mg fenofibrate for combined dyslipidemia: total cholesterol 194 mg/dl, LDL cholesterol 115 mg/dl, HDL cholesterol 32 mg/dl, and triglycerides 229 mg/dl. Medications at that time included 40 mg simvastatin, 50 mg atenolol, 0.112 mg levothyroxine, 8 mg rosiglitazone, 150 mg ranitidine twice daily, and 5 mg terazosin. Laboratory values before starting fenofibrate were serum creatinine 1.6 mg/dl, creatinine phosphokinase (CPK) 200 IU/l, and normal liver profile. He denied having any recent illness or alcohol, antibiotic, or over-the-counter medication use. Serum laboratory values at presentation were creatinine 2.7 mg/dl and CPK 10,936 IU/l. Urine was dark yellow with 3+ blood and trace protein. Fenofibrate and simvastatin were discontinued, and the patient was admitted with rhabdomyolysis. With hydration, his myalgia resolved and creatinine returned to baseline within 1 week. Serum CPK peaked at 15,000 IU/l and returned to baseline within 4 weeks.

The mechanism of muscle damage is unclear, but the risk of serious interaction with simvastatin-fenofibrate combination is not completely absent. Trials have shown fewer side effects with this combination, but they are limited by small sample sizes, exclusion of patients predisposed to adverse events, and short-term follow-ups (1,3).

At this juncture, two aspects need to be revisited: evidence of advantage and safety of this combination compared with simvastatin or fenofibrate monotherapy. To date, there is neither evidence to support a reduction in coronary artery disease outcome nor sufficient data to make conclusions regarding the safety of this combination. Hence, physicians need to be aware of potentially fatal side effects such as rhabdomyolysis when prescribing simvastatin-fenofibrate combination. In addition, careful selection and monitoring of patients, patient education on risk and warning symptoms of potential adverse effects, and screening for risk factors such as hepatic impairment, renal insufficiency, serious infections, hypothyroidism, and diabetes, especially in elderly patients, is warranted. Data from large long-term trials like the ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial are needed to establish both the efficacy and the safety of this combination in treating combined dyslipidemia.