Can fenofibrate (fibric acid derivative) increase liver enzymes?

Fenofibrate Can Increase Liver Enzymes

Yes, fenofibrate can increase liver enzymes, and patients taking this medication should have annual liver enzyme monitoring. 1, 2

Mechanism and Frequency of Liver Enzyme Elevation

• Fenofibrate is associated with elevations in liver transaminases in clinical trials, with abnormal liver function tests occurring in 7.5% of patients taking fenofibrate compared to 1.4% on placebo 2
• In a pooled analysis of 10 placebo-controlled trials, increases to >3 times the upper limit of normal in ALT occurred in 5.3% of patients taking fenofibrate at doses equivalent to 107-160 mg daily versus 1.1% of patients treated with placebo 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 higher doses (107-160 mg daily) and 0% in those receiving lower doses (≤54 mg) or placebo 2

Monitoring Recommendations

• The American Geriatrics Society recommends that patients taking a fibrate should have an annual evaluation of liver enzymes 1
• For patients newly prescribed fenofibrate, liver function tests should be monitored at baseline and periodically for the duration of therapy 2
• For elevations less than 3-fold the upper limit of normal, repeat testing should be done in 2-4 weeks 3
• For significant elevations in liver enzymes (≥3-fold the upper limit of normal), close monitoring, repeat testing in 2-4 weeks, and dose decrease as needed are recommended 3

Management of Elevated Liver Enzymes

• If there is a confirmed increase in ALT/AST greater than three times the upper limit of normal, fenofibrate should be discontinued 2
• The medication may be reinstituted at a lower dose following normalization of liver enzymes 2
• For persistent elevations during a 12-month period or a decline in serum albumin below the normal range in a patient with normal nutritional status, consultation with gastroenterology should be considered 3

Timing and Pattern of Liver Enzyme Elevation

• Liver enzyme elevations can occur with variable latency after starting fenofibrate:
  • Short latency (5-8 weeks) in some patients
  • More prolonged latency (18-56 weeks) in others 4
• Early increases in liver enzymes may be observed in the first 4 weeks after initiating treatment, particularly in patients already taking statins 1
• These early elevations often return to normal within approximately 8 weeks after initiating treatment, even without discontinuation 1

Risk Factors and Special Considerations

• Patients with pre-existing liver disease are at higher risk and require more careful monitoring 2
• The combination of fenofibrate with statins does not appear to significantly increase the risk of hepatotoxicity beyond that of fenofibrate alone 3
• However, when using fenofibrate in combination with statins, there is an increased risk of myopathy 3
• In patients with chronic kidney disease (CKD), dose adjustment is necessary, and fenofibrate should be avoided in CKD stages 4-5 1

Clinical Implications and Pitfalls

• Increases in liver function tests were the most frequent adverse events causing discontinuation of fenofibrate treatment in 1.6% of patients in double-blind trials 2
• Although most cases of fenofibrate-induced liver injury are self-limited, severe injury and mortality can occur, particularly if drug withdrawal is delayed 4
• Jaundice or abnormal laboratory tests during fenofibrate therapy should trigger prompt discontinuation 4
• Routine monitoring is essential as some patients with fenofibrate-induced liver injury may not undergo routine monitoring, potentially leading to delayed diagnosis 4

By following appropriate monitoring protocols and promptly addressing any significant elevations in liver enzymes, the risk of serious hepatotoxicity from fenofibrate can be minimized while still allowing patients to benefit from its lipid-lowering effects.