Can Fenofibrate and Zetia (Ezetimibe) be taken together?

Fenofibrate and Ezetimibe Can Be Safely Taken Together

Yes, fenofibrate and ezetimibe (Zetia) can be safely taken together and this combination is specifically approved for treating mixed hyperlipidemia. 1 This combination offers complementary mechanisms for managing dyslipidemia with a favorable safety profile compared to other fibrate-based combinations.

Safety Profile of the Combination

• Unlike gemfibrozil (another fibrate), fenofibrate has a significantly lower risk of adverse effects when combined with other lipid-lowering medications:
  • The FDA Adverse Event Reporting System shows rhabdomyolysis reports are approximately 15 times lower for fenofibrate than for gemfibrozil when combined with other lipid medications (0.58 vs 8.6 per million prescriptions) 2
  • The FDA label specifically indicates ezetimibe is approved "in combination with fenofibrate as an adjunct to diet to reduce elevated LDL-C in adults with mixed hyperlipidemia" 1

Mechanism and Benefits

The combination works through complementary mechanisms:

• Ezetimibe: Inhibits intestinal cholesterol absorption by targeting the NPC1L1 protein
• Fenofibrate: Activates peroxisome proliferator-activated receptors (PPARs), reducing triglycerides and increasing HDL-C

When used together, they provide more comprehensive lipid management than either agent alone:

• Greater LDL-C reduction than either monotherapy 3
• Significant triglyceride reduction (comparable to fenofibrate alone) 3
• Improved HDL-C levels 3
• Better overall non-HDL-C reduction 3

Important Precautions

While the combination is safe, there are some considerations:

• Both fenofibrate and ezetimibe may increase cholesterol excretion into bile, potentially increasing risk of cholelithiasis (gallstones) 1
• If cholelithiasis is suspected, gallbladder studies should be performed and alternative therapy considered 1
• Fenofibrate may increase ezetimibe bioavailability by approximately 48% 4, but this is not considered clinically significant due to ezetimibe's established safety profile and flat dose-response

Monitoring Recommendations

When using this combination:

1. Obtain baseline liver function tests before initiating therapy 5
2. Monitor liver enzymes periodically, especially during initial treatment 5
3. Instruct patients to report muscle symptoms promptly 5
4. Monitor lipid profile regularly to assess efficacy 5

Comparison to Other Combinations

The 2016 American Heart Association scientific statement specifically recommends:

• "When statin-fibrate combination therapy is indicated, fenofibrate or fenofibric acid is preferred because of a reduced incidence of drug-drug interactions compared with statin-gemfibrozil combination therapy" 2
• "The use of gemfibrozil should be avoided in combination with lovastatin, pravastatin, and simvastatin" 2

Clinical Evidence

Clinical studies support the safety and efficacy of this combination:

• A randomized controlled trial of patients with mixed hyperlipidemia showed the fenofibrate-ezetimibe combination significantly improved the overall atherogenic lipid profile compared to either agent alone 6
• In patients with type 2 diabetes and mixed hyperlipidemia, the combination effectively improved lipid parameters with good tolerability 7

In conclusion, fenofibrate and ezetimibe can be safely taken together and represent an effective combination for managing mixed hyperlipidemia, particularly in patients who cannot tolerate statins or require additional lipid management beyond statin therapy.