What are the adverse effects and mechanism of action (MOA) of fenofibrate?

Fenofibrate: Mechanism of Action and Adverse Effects

Fenofibrate is a fibric acid derivative that reduces triglycerides but has significant adverse effects including increased risk of myopathy (especially when combined with statins), elevated liver enzymes, increased creatinine, and cholelithiasis. 1

Mechanism of Action

Fenofibrate works primarily through activation of peroxisome proliferator-activated receptor-alpha (PPAR-α), which leads to:

• Decreased hepatic production and release of very low-density lipoprotein (VLDL) 2
• Increased lipolysis and elimination of triglyceride-rich particles 2
• Increased production of high-density lipoprotein (HDL) and apolipoprotein A1 2
• Reduction in small, dense LDL particles and shift to larger, more buoyant LDL particles 2

Major Adverse Effects

Renal Effects

• Elevations in serum creatinine that typically return to baseline after discontinuation 1
• Requires monitoring of renal function, especially in patients with:
  • Pre-existing renal impairment
  • Elderly patients
  • Patients with diabetes 1
• Contraindicated in severe renal impairment (GFR <30 mL/min/1.73 m²) 3

Hepatic Effects

• Risk of hepatotoxicity with elevated liver enzymes 1
• In clinical trials, increases to >3 times the upper limit of normal in ALT occurred in 5.3% of patients taking fenofibrate versus 1.1% with placebo 1
• Requires regular monitoring of liver function tests 1

Musculoskeletal Effects

• Risk of myopathy and rhabdomyolysis, particularly when combined with statins 1
• Higher risk in patients with:
  • Diabetes
  • Renal impairment
  • Hypothyroidism
  • Elderly patients 3
• Gemfibrozil has higher risk of myopathy when combined with statins than fenofibrate 3

Gastrointestinal Effects

• Increased risk of cholelithiasis (gallstones) due to increased cholesterol excretion into bile 1
• Abdominal pain (4.6% vs 4.4% with placebo) 1
• Nausea (2.3% vs 1.9% with placebo) 1
• Constipation (2.1% vs 1.4% with placebo) 1
• Risk of pancreatitis 1

Hematologic Effects

• Mild to moderate decreases in hemoglobin, hematocrit, and white blood cell counts 1
• Thrombocytopenia and agranulocytosis have been reported 1
• Periodic monitoring of blood counts recommended during first 12 months 1

Cardiovascular Effects

• Increased risk of venothromboembolic events:
  • Higher rates of pulmonary embolism (1% vs 0.7% with placebo) 1
  • Higher rates of deep vein thrombosis (1% vs 0.7% with placebo) 1

Hypersensitivity Reactions

• Acute hypersensitivity: anaphylaxis and angioedema 1
• Delayed hypersensitivity: severe cutaneous adverse reactions including Stevens-Johnson syndrome, toxic epidermal necrolysis, and DRESS syndrome 1
• Photosensitivity reactions reported days to months after initiation 1

Other Effects

• Paradoxical decreases in HDL cholesterol levels (rare but severe) 1
• Increased risk of bleeding when combined with anticoagulants 1
• May increase uric acid levels and risk of gout 4

Drug Interactions

• Potentiates effects of coumarin anticoagulants, requiring careful monitoring of INR 1
• Increased risk of myopathy when combined with statins or colchicine 1
• Interactions with immunosuppressants like cyclosporine and tacrolimus may worsen renal function 1

Monitoring Recommendations

1. Baseline and periodic monitoring of:

   • Liver function tests
   • Renal function
   • Complete blood count
   • Creatine phosphokinase (CPK)
   • Lipid profile 1

2. Monitor HDL-C levels within first few months of therapy to detect paradoxical decreases 1

3. More frequent monitoring in high-risk patients (elderly, diabetics, renal impairment) 3

Fenofibrate remains a valuable option for managing hypertriglyceridemia, but requires careful patient selection and monitoring to minimize the risk of adverse effects.