What is the interaction between Fenofibrate and Ezetimibe (Zetia)?

From the Guidelines

Fenofibrate and ezetimibe can be used together to manage dyslipidemia, particularly in patients with mixed dyslipidemia and elevated LDL cholesterol and triglycerides, as evidenced by the 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults 1. When using this combination, it is essential to consider the potential benefits and risks. Fenofibrate primarily reduces triglycerides and increases HDL cholesterol by activating peroxisome proliferator-activated receptor alpha (PPAR-α), while ezetimibe lowers LDL cholesterol by inhibiting intestinal cholesterol absorption. Some key points to consider when using fenofibrate and ezetimibe together include:

• A typical regimen includes fenofibrate 145 mg once daily and ezetimibe 10 mg once daily, taken with or without food.
• Baseline liver function tests and lipid panels should be obtained, with follow-up testing after 6-12 weeks to assess efficacy and monitor for side effects.
• Patients should be aware of potential side effects including muscle pain, liver enzyme elevations, and gallstone formation.
• This combination is particularly useful for mixed dyslipidemia with elevated LDL cholesterol and triglycerides, especially in patients with metabolic syndrome or diabetes.
• Regular monitoring of liver function, kidney function, and muscle symptoms is essential during treatment, as fenofibrate-simvastatin has been associated with increased ALT >5 times ULN and increased creatinine level 1.
• Lifestyle modifications including diet, exercise, and smoking cessation should continue alongside medication therapy for optimal results. It is also important to note that the European guidelines on cardiovascular disease prevention in clinical practice recommend using combination treatment, including statins and ezetimibe or fibrates, to achieve greater reduction of LDL cholesterol and to minimize the risk of adverse effects associated with high doses of statins 1.

From the FDA Drug Label

Combination with Fenofibrate This clinical trial involving 625 patients with mixed dyslipidemia (age range 20 to 76 years; 44% female, 79% White, 1% Black or African American, 20% other races; 11% identified as Hispanic or Latino ethnicity) treated for up to 12 weeks and 576 patients treated for up to an additional 48 weeks evaluated coadministration of ezetimibe tablets and fenofibrate. Incidence rates for clinically important elevations (≥3 X ULN, consecutive) in hepatic transaminase levels were 4.5% and 2.7% for fenofibrate monotherapy (n=188) and ezetimibe tablets coadministered with fenofibrate (n=183), respectively, adjusted for treatment exposure.

The combination of Fenofibrate and Ezetimibe may increase the risk of cholelithiasis due to increased cholesterol excretion into the bile.

• The incidence of elevated hepatic transaminase levels was lower in patients receiving ezetimibe and fenofibrate (2.7%) compared to those receiving fenofibrate monotherapy (4.5%).
• If cholelithiasis is suspected in a patient receiving ezetimibe and fenofibrate, gallbladder studies are indicated, and alternative lipid-lowering therapy should be considered 2.

From the Research

FEnofibrate and Ezitimibe Combination Therapy

• The combination of fenofibrate and ezetimibe has been studied in several clinical trials to evaluate its efficacy and safety in patients with mixed dyslipidemia and metabolic syndrome 3, 4, 5.
• The results of these studies suggest that the combination of fenofibrate and ezetimibe produces complementary and favorable effects on lipid parameters, including low-density lipoprotein cholesterol (LDL-C), triglycerides, and high-density lipoprotein cholesterol (HDL-C) 3, 4.
• Fenofibrate alone has been shown to reduce triglycerides and increase HDL-C, while ezetimibe alone has been shown to reduce LDL-C 3, 4.
• The combination of fenofibrate and ezetimibe has been found to be more effective than either monotherapy in reducing LDL-C, non-HDL-C, and apolipoprotein B, and in increasing HDL-C in patients with low baseline HDL-C levels 5.

Mechanisms of Action

• Fenofibrate works by activating peroxisome proliferator-activated receptor-alpha (PPAR-alpha), which regulates the expression of genes involved in lipid metabolism 6, 7.
• Ezetimibe works by inhibiting the intestinal absorption of cholesterol, which reduces the amount of cholesterol available for incorporation into LDL particles 4, 5.
• The combination of fenofibrate and ezetimibe may offer a synergistic effect on lipid metabolism, with fenofibrate reducing triglycerides and increasing HDL-C, and ezetimibe reducing LDL-C 4, 5.

Clinical Utility

• The combination of fenofibrate and ezetimibe may be a useful treatment option for patients with mixed dyslipidemia and metabolic syndrome who require more aggressive treatment of multiple lipid parameters 3, 5.
• Fenofibrate may be preferred over other fibrates, such as gemfibrozil, due to its lower risk of rhabdomyolysis when used in combination with a statin 6.
• The role of fenofibrate-statin therapy and other therapies involving fenofibrate in cardiovascular risk reduction strategies remains to be established 7.