Can fenofibrate increase Liver Function Tests (LFTs)?

Fenofibrate Can Increase Liver Function Tests

Yes, fenofibrate can significantly increase liver function tests (LFTs) and has been documented to cause hepatotoxicity in some patients. 1 According to the FDA drug label, increases in liver enzymes are among the most common adverse reactions leading to discontinuation of fenofibrate treatment in clinical trials.

Mechanism and Evidence of Liver Enzyme Elevation

• In pooled analysis of placebo-controlled trials, increases to >3 times the upper limit of normal in ALT occurred in 5.3% of patients taking fenofibrate at therapeutic doses versus only 1.1% of patients on placebo 1
• Fenofibrate at high doses inhibits some CYP enzymes, particularly CYP2C9, which may contribute to hepatotoxicity 2
• At therapeutic doses, fibric acid derivatives increase serum alanine transaminase (ALT) and AST levels, which may relate to known transcriptional effects on liver transaminase synthesis 2
• In an 8-week study, the incidence of ALT or AST elevations ≥3 times the upper limit of normal was 13% in patients receiving standard therapeutic doses of fenofibrate 1

Risk Factors for Fenofibrate-Induced Liver Enzyme Elevation

Several factors have been identified that increase the risk of fenofibrate-induced liver enzyme elevation:

• Higher BMI 3
• Elevated baseline serum triglycerides 3
• Elevated baseline ALP 3
• Elevated baseline gamma-GTP levels 3
• Female sex (women with well-controlled diabetes who received fenofibrate-simvastatin had higher cardiovascular event rates compared to simvastatin alone) 2

Timing and Presentation of Liver Injury

• Most cases of liver enzyme elevation occur within weeks to months after starting therapy
• However, severe cases can develop rapidly - one case report documented significant liver injury within 48 hours after first administration 4
• Latency period can vary widely:
  • Short latency (5-8 weeks) in some patients
  • More prolonged latency (18-56 weeks) in others 5

Severity and Outcomes

• Most elevations in liver enzymes are mild and transient
• However, severe injury can occur, particularly if drug withdrawal is delayed 5
• Among documented cases of drug-induced liver injury (DILI), fenofibrate accounts for approximately 0.6% of cases 5
• Severe outcomes reported include:
  • Need for liver transplantation
  • Development of chronic liver injury
  • Death in rare cases 5

Monitoring and Management

• The FDA drug label indicates that increases in liver enzymes were the most frequent events causing discontinuation of fenofibrate treatment (1.6% of patients in double-blind trials) 1
• Regular monitoring of liver function is recommended:
  • Baseline liver function tests before starting therapy
  • Follow-up tests within 3 months after initiation
  • Periodic monitoring thereafter 6
• If severely elevated liver enzymes are detected, fenofibrate should be withdrawn immediately 1
• After discontinuation, liver enzymes typically return to normal within 2-4 weeks 4

Special Considerations

• Combination therapy with statins: When combining fenofibrate with statins, there is an increased risk of myopathy, but the combination doesn't appear to significantly increase the risk of liver enzyme elevations beyond what is seen with either agent alone 2
• Renal impairment: Patients with renal impairment require dose adjustment, as impaired clearance may increase risk of adverse effects, including liver enzyme elevations 2
• Pre-existing liver disease: Caution should be exercised in patients with pre-existing liver disease, as fenofibrate may exacerbate underlying conditions 2

Conclusion

Fenofibrate therapy requires careful monitoring of liver function tests due to its known potential to cause liver enzyme elevations. While most cases are mild and resolve with discontinuation, severe hepatotoxicity can occur. Prompt discontinuation of the medication when significant liver enzyme elevations are detected is essential to prevent progression to more severe liver injury.