Can gemfibrozil increase creatine (CK) kinase levels?

Gemfibrozil Can Increase Creatine Kinase Levels

Yes, gemfibrozil can increase creatine kinase (CK) levels, particularly when used as monotherapy and especially when combined with statins, which significantly increases the risk of muscle-related toxicity including myopathy and rhabdomyolysis. 1, 2

Mechanism of Gemfibrozil-Induced CK Elevation

• Gemfibrozil monotherapy is associated with a 5.5-fold increased risk of muscle-related toxicity compared with statin therapy alone 1
• The FDA drug label specifically notes that gemfibrozil use may be associated with myositis, which manifests with elevated creatine kinase levels 2
• Gemfibrozil can cause direct muscle damage through mechanisms that are not fully understood, but may involve:
  • Disruption of normal cellular respiration in muscle cell mitochondria 1
  • Interaction with drug metabolism pathways, particularly when combined with other medications 1

Clinical Evidence of Gemfibrozil-Induced CK Elevation

• Case reports document gemfibrozil monotherapy causing myositis with significantly elevated CK levels (up to 3495 U/L) even in patients with normal renal function 3
• The FDA drug label specifically lists increased CPK (creatine phosphokinase) among the symptoms reported with gemfibrozil overdose 2
• Rhabdomyolysis with markedly elevated CK levels has been reported with gemfibrozil monotherapy 4

Risk Factors for Gemfibrozil-Induced CK Elevation

• Renal impairment significantly increases the risk of myopathy and CK elevation with gemfibrozil 5
• Strenuous exercise can exacerbate gemfibrozil-induced muscle damage and CK elevation 4, 6
• Combination therapy with statins dramatically increases the risk:
  • Reports of muscle symptoms were 15.7 per 1 million prescriptions for gemfibrozil compared to 8.8 per 1 million for fenofibrate 1
  • The rate of gemfibrozil-associated rhabdomyolysis was approximately 10-fold higher compared with fenofibrate 1

Statin-Gemfibrozil Combination and CK Elevation

• The combination of gemfibrozil with statins significantly increases the risk of muscle toxicity and CK elevation through both pharmacokinetic and pharmacodynamic mechanisms 1
• Gemfibrozil inhibits several key pathways:
  • Potent irreversible inhibitor of CYP2C8 1
  • Inhibits OATP1B1/3-mediated hepatic uptake of statins 1
  • Inhibits statin glucuronidation or lactonization 1
• These interactions lead to increased statin concentrations:
  • Increases AUC of simvastatin and lovastatin acid by 2-3 fold 1
  • Increases pravastatin concentrations by 202% (range 40%-412%) 1
  • Increases rosuvastatin concentrations by 1.56-1.88 fold 1

Monitoring and Management

• All patients taking gemfibrozil should be instructed to report muscle discomfort, weakness, or brown urine immediately 1
• If myositis is suspected based on symptoms and elevated CK, gemfibrozil therapy should be withdrawn 2
• Routine CK monitoring is of little value in asymptomatic patients 1
• If gemfibrozil must be used with statins (not recommended), fenofibrate is preferred over gemfibrozil due to lower risk of drug interactions 1
• Gemfibrozil should be avoided in combination with lovastatin, pravastatin, and simvastatin 1

Special Considerations

• Fluvastatin may be safer to use in combination with gemfibrozil if combination therapy is absolutely necessary 1, 7
• Patients with normal renal function can still develop significant CK elevation with gemfibrozil monotherapy 3
• The American Heart Association recommends avoiding gemfibrozil-statin combinations when possible due to the increased risk of muscle toxicity 1