What is the mechanism of action of fenofibrate?

Mechanism of Action of Fenofibrate

Fenofibrate works primarily by activating peroxisome proliferator-activated receptor alpha (PPARα), which regulates genes involved in lipid metabolism, particularly targeting triglyceride-rich lipoproteins. 1

Primary Mechanism

Fenofibrate is a pro-drug that is converted by ester hydrolysis in the body to fenofibric acid, which is the active constituent. The lipid-modifying effects occur through several key processes:

1. PPARα Activation:

   • Fenofibric acid activates PPARα in the liver, which regulates the transcription of genes involved in lipid metabolism 1
   • This activation has been demonstrated in vivo in transgenic mice and in vitro in human hepatocyte cultures 1

2. Effects on Triglyceride Metabolism:

   • Increases lipolysis and elimination of triglyceride-rich particles from plasma
   • Activates lipoprotein lipase
   • Reduces production of apoprotein C-III (an inhibitor of lipoprotein lipase activity) 1

3. Effects on LDL Particles:

   • Alters the size and composition of LDL from small, dense particles (which are more atherogenic due to their susceptibility to oxidation) to large buoyant particles
   • These larger particles have greater affinity for cholesterol receptors and are catabolized more rapidly 1

4. Effects on HDL Metabolism:

   • Induces increased synthesis of apolipoproteins A-I and A-II
   • Increases HDL-cholesterol levels 1

5. Additional Effects:

   • Reduces serum uric acid levels by increasing urinary excretion of uric acid 1

Clinical Effects on Lipid Profile

Fenofibrate treatment results in:

• Reduction in total triglycerides
• Reduction in triglyceride-rich lipoproteins (VLDL)
• Reduction in total cholesterol
• Reduction in LDL cholesterol
• Reduction in apolipoprotein B
• Increase in HDL cholesterol
• Increase in apolipoproteins A-I and A-II 1

Pharmacokinetics

• Fenofibrate is well absorbed from the gastrointestinal tract
• Absorption increases approximately 35% when taken with food
• Peak plasma levels occur within 6-8 hours after administration
• Steady-state is achieved within 5 days of multiple dosing
• Approximately 60% of a dose appears in urine (primarily as fenofibric acid and its glucuronate conjugate)
• 25% is excreted in feces 1

Clinical Implications

While fenofibrate effectively improves lipid profiles, particularly in patients with elevated triglycerides and low HDL-C, clinical outcomes have been mixed:

• In the FIELD study, fenofibrate showed a significant 24% reduction in nonfatal MI but no significant reduction in the primary endpoint of coronary events 2
• Fenofibrate has shown benefit in reducing microvascular complications in diabetes, including less albuminuria progression and less retinopathy requiring laser treatment 2
• The drug appears most beneficial in patients with atherogenic dyslipidemia (high triglycerides and low HDL-C) 2

Potential Pitfalls and Considerations

1. Combination with Statins:

   • When used with statins, monitor for risk of myositis and rhabdomyolysis 2
   • Fenofibrate plus simvastatin has shown no significant benefit in the primary outcome of cardiovascular events in the ACCORD trial 2

2. Renal Function:

   • Fenofibrate can cause a temporary rise in serum creatinine 2
   • Dose reduction is required in patients with mild to moderate renal impairment
   • Should be avoided in severe renal impairment 1

3. Patient Selection:

   • Greatest benefit appears to be in patients with both high triglycerides and low HDL-C 2
   • Limited evidence supporting use in non-dyslipidemic patients 2

Understanding fenofibrate's mechanism of action helps explain its clinical effects and guides appropriate patient selection for therapy, focusing on those most likely to benefit from its unique effects on lipid metabolism.