Fenofibrate and Simvastatin Combination Safety
When statin-fibrate combination therapy is indicated, fenofibrate is preferred over gemfibrozil due to a significantly lower risk of myopathy and drug interactions with simvastatin. 1
Safety Profile of Fenofibrate-Simvastatin Combination
- Fenofibrate-simvastatin combination therapy has similar rates as simvastatin alone for myopathy, myositis, or rhabdomyolysis; CK or ALT elevations, renal disease requiring hemodialysis; cancer death; or pulmonary embolism/thrombosis 1
- Reports of rhabdomyolysis are approximately 15 times lower for fenofibrate than for gemfibrozil when prescribed with statins (0.58 vs 8.6 cases per 1 million prescriptions) 1, 2
- In the FIELD study, none of the approximately 1,000 patients on statin-fenofibrate combination therapy experienced rhabdomyolysis 1, 2
- The ACCORD study showed no statistically significant differences in the incidence of myositis, rhabdomyolysis, or elevated hepatic transaminases with simvastatin-fenofibrate combination compared to simvastatin alone in patients with type 2 diabetes 1
Important Safety Considerations
- Fenofibrate-simvastatin combination was more likely to increase ALT >5 times upper limit of normal and increase creatinine levels compared to simvastatin alone 1
- Meta-analysis of clinical trials showed that the incidence of alanine aminotransferase and/or aspartate aminotransferase ≥3 times upper limit of normal was significantly higher with combination therapy than with statin monotherapy (3.1% vs 0.2%, p = 0.0009) 3
- Rare but serious cases of rhabdomyolysis-induced acute renal failure have been reported with fenofibrate-statin combinations, particularly in patients with risk factors 4
Risk Factors for Myopathy with Combination Therapy
- Advanced age (especially >80 years), with women at higher risk than men 2, 5
- Small body frame and frailty 2
- Chronic renal insufficiency, especially due to diabetes 2, 5
- Multiple medications 2
- Perioperative periods 2
Clinical Efficacy Considerations
- In adults with diabetes, CVD, and/or CVD risk factors, fenofibrate added to simvastatin did not additionally reduce LDL-C but minimally increased HDL-C (1 mg/dL or 2%) and moderately reduced triglycerides (23 mg/dL or 14%) 1
- In the overall population, fenofibrate-simvastatin did not reduce the risk for CVD events compared with simvastatin alone 1
- Patients with triglycerides ≥204 mg/dL and HDL-C ≥40 mg/dL may experience a reduction in CVD events from fenofibrate-simvastatin compared with simvastatin alone 1
- CVD event rates were higher in women with well-controlled diabetes who received fenofibrate-simvastatin compared with simvastatin alone 1
Recommendations for Clinical Practice
- When statin-fibrate combination therapy is indicated, fenofibrate or fenofibric acid is preferred over gemfibrozil 1, 2
- Fenofibrate can be safely combined with simvastatin when clinically indicated, but careful monitoring is required 1, 2
- Start with low doses of statin when combining with fenofibrate 2
- Monitor liver function tests before starting fenofibrate, within 3 months after initiation, and periodically thereafter 5
- Monitor patients for muscle symptoms, which may include pain, tenderness, or weakness 2, 5
- Consider withholding statin therapy during periods of major surgery 2
- Use caution in elderly patients, particularly older thin or frail women 2
- Monitor carefully in patients with diabetes combined with chronic renal failure 2, 5
Pharmacokinetic Interactions
- Studies have shown no clinically significant pharmacokinetic interaction between fenofibrate and simvastatin at steady state 6
- The geometric mean ratios for AUC(0-24h) for active and total HMG-CoA reductase inhibitors when simvastatin was combined with fenofibrate versus simvastatin alone were 0.88 and 0.92, respectively, indicating no significant interaction 6
Despite the relative safety of fenofibrate-simvastatin combination compared to other fibrate-statin combinations, current guidelines from the American Diabetes Association note that statin plus fibrate combination therapy has not been shown to improve atherosclerotic cardiovascular disease outcomes and is generally not recommended 1.