What are the side effects of fibrate therapy?

Side Effects of Fibrate Therapy

Fibrates are associated with significant risk of muscle-related toxicity, liver enzyme elevations, and increased risk of venothromboembolic events, with gemfibrozil carrying higher risk than fenofibrate, especially when combined with statins. 1

Common Side Effects

Muscle-Related Toxicity

• Myopathy and muscle-related toxicity are the most concerning adverse effects 1
• Risk of muscle toxicity is 5.5-fold higher with fibrates compared to statin monotherapy 1
• Symptoms range from muscle pain and tenderness to severe myositis
• Risk factors for myopathy include:
  • Combination with statins (particularly gemfibrozil with statins)
  • Renal insufficiency
  • Advanced age
  • Multiple medications

Hepatic Effects

• Elevated liver transaminases (ALT, AST) occur in up to 7.5% of patients 2
• Liver function tests should be monitored every 3-6 months 1
• Severe hepatotoxicity is rare but possible

Gastrointestinal Effects

• Gastrointestinal upset is common 1
• Abdominal pain (4.6% vs 4.4% for placebo) 2
• Nausea (2.3% vs 1.9% for placebo) 2
• Constipation (2.1% vs 1.4% for placebo) 2
• Increased predisposition to cholelithiasis (gallstones) 1

Hematologic Effects

• Mild to moderate decreases in hemoglobin, hematocrit, and white blood cell counts 2
• Thrombocytopenia and agranulocytosis have been reported 2
• Periodic monitoring of blood counts recommended during first 12 months 2

Serious Side Effects

Venothromboembolic Disease

• Increased risk of pulmonary embolism and deep vein thrombosis 2
• In the FIELD trial, pulmonary embolism events were higher with fenofibrate (1%) compared to placebo (0.7%) (p=0.022) 2
• DVT events were 1% with fenofibrate vs 1% with placebo (p=0.074) 2

Pancreatitis

• Reported with all fibrates (fenofibrate, gemfibrozil, clofibrate) 2
• May represent direct drug effect or secondary phenomenon through biliary tract stone formation 2

Hypersensitivity Reactions

• Acute reactions including anaphylaxis and angioedema (can be life-threatening) 2
• Delayed hypersensitivity including severe cutaneous adverse reactions (SCAR) 2
• Stevens-Johnson syndrome, toxic epidermal necrolysis, and DRESS syndrome reported 2

Paradoxical HDL-C Decreases

• Severe decreases in HDL cholesterol levels (as low as 2 mg/dL) reported 2
• Can occur within 2 weeks to years after starting therapy 2
• Monitoring of HDL-C recommended within first few months of treatment 2

Drug Interactions

Anticoagulants

• Potentiation of coumarin-type anticoagulant effects 2
• Increased risk of bleeding complications 2
• Frequent monitoring of PT/INR and dose adjustment recommended 2

Statin Combinations

• Significantly increased risk of myopathy and rhabdomyolysis 1
• Risk is higher with gemfibrozil than fenofibrate 1
• Gemfibrozil is contraindicated with simvastatin 1
• The ACCORD study showed no cardiovascular benefit of adding fenofibrate to simvastatin 1

Monitoring Recommendations

1. Liver function tests (ALT, AST) every 3-6 months 1
2. Complete blood count monitoring during first 12 months 2
3. HDL-C levels within first few months of therapy 2
4. Creatine kinase if muscle symptoms develop 1
5. PT/INR if combined with anticoagulants 2

Special Considerations

• Fibrates should be used preferentially for children with severe triglyceride elevations who are at risk for pancreatitis 1
• Fenofibrate increases serum creatinine but this is not associated with renal impairment 1
• Gemfibrozil has approximately 10-fold higher risk of rhabdomyolysis compared to fenofibrate when combined with statins 1
• Fibrates should be used with caution in patients with renal insufficiency due to increased risk of adverse effects 1

Practical Approach to Fibrate Use

1. Reserve fibrates primarily for severe hypertriglyceridemia (≥500 mg/dL) to reduce pancreatitis risk 1
2. Prefer fenofibrate over gemfibrozil when combination with statins is necessary 1
3. Discontinue fibrate and seek medical attention if signs of hypersensitivity develop 2
4. Consider discontinuation if HDL-C levels decrease severely 2
5. Avoid fibrates in patients with history of gallbladder disease when possible 1