Is it safe to use fenofibrate with a statin, such as atorvastatin (lipitor) or simvastatin (zocor), for treating hypertriglyceridemia or mixed dyslipidemia?

Fenofibrate with Statin: Safety and Recommendations

When statin-fibrate combination therapy is indicated, fenofibrate or fenofibric acid is preferred over gemfibrozil because of a reduced incidence of drug-drug interactions and lower risk of myopathy. 1

Safety of Fenofibrate-Statin Combination

• Fenofibrate-statin combination therapy is generally safe when used appropriately, with reports of rhabdomyolysis approximately 15 times lower for fenofibrate than for gemfibrozil when prescribed with statins (0.58 vs 8.6 cases per 1 million prescriptions) 1
• In the FIELD study (n=9795), none of the approximately 1,000 patients on statin-fenofibrate combination therapy experienced rhabdomyolysis 1
• The ACCORD study showed no statistically significant differences in the incidence of myositis, rhabdomyolysis, or elevations of hepatic transaminases with simvastatin-fenofibrate combination therapy compared to simvastatin monotherapy in patients with type 2 diabetes 1
• A meta-analysis of 6 randomized controlled trials with 1,628 subjects reported no cases of myopathy or rhabdomyolysis with statin-fenofibrate combination therapy 2

Specific Statin-Fibrate Recommendations

Preferred Combinations:

• Fenofibrate can be safely combined with any statin when clinically indicated 1
• Fluvastatin may be used in combination with either gemfibrozil, fenofibrate, or fenofibric acid 1

Combinations to Avoid:

• Gemfibrozil should be avoided in combination with lovastatin, pravastatin, and simvastatin 1
• FDA-approved product labeling indicates that gemfibrozil is contraindicated with simvastatin 1

Monitoring Recommendations

• Monitor patients for muscle symptoms, which may include pain, tenderness, or weakness 1
• Check baseline liver function tests and creatine kinase (CK) levels 1
• More frequent CK measurements are indicated for patients with moderate CK elevations (3-10 times upper limit of normal) 1
• Patients with risk factors for myopathy require closer monitoring 1, 3

Risk Factors for Statin-Fibrate Associated Myopathy

• Advanced age (especially >80 years), with women at higher risk than men 1
• Small body frame and frailty 1
• Multisystem disease (e.g., chronic renal insufficiency, especially due to diabetes) 1
• Multiple medications 1
• Perioperative periods 1

Clinical Efficacy

• Combined therapy with fenofibrate and statin is more effective than monotherapy for mixed hyperlipidemia 4, 5
• In patients with mixed hyperlipidemia, combination therapy has shown significant improvements in total cholesterol, LDL-C, HDL-C, and triglyceride levels 4, 5
• However, the 2023 Diabetes Care guidelines note that statin plus fibrate combination therapy has not been shown to improve atherosclerotic cardiovascular disease outcomes and is generally not recommended 1

Practical Approach to Combination Therapy

• Start with low doses of statin when combining with fenofibrate 3
• Standard fenofibrate dosing is 54-160 mg daily when used in combination therapy 3
• Consider withholding statin therapy during periods of major surgery 1
• Use caution in elderly patients, particularly older thin or frail women 1, 3
• Monitor carefully in patients with diabetes combined with chronic renal failure 1

Important Caveats

• The combination of statin and fibrate is associated with an increased risk for abnormal transaminase levels, with liver enzyme elevations (ALT/AST ≥3 times ULN) significantly higher in combination therapy (3.1%) compared to statin monotherapy (0.2%) 2
• The risk of rhabdomyolysis is more common with higher doses of statins and in patients with renal insufficiency 1
• Combination therapy should be reserved for cases where the benefits from ASCVD risk reduction or triglyceride lowering (especially when triglycerides are ≥500 mg/dL) outweigh the potential risks 1