Does ezetimibe increase creatine kinase (CK) levels similar to statins (HMG-CoA reductase inhibitors)?

From the Guidelines

Ezetimibe does not significantly increase creatine kinase (CK) levels, unlike statins, due to its distinct mechanism of action in the intestine, blocking cholesterol absorption. The most recent and highest quality study, 1, supports this statement, as it notes that adverse reactions to ezetimibe are mild and transient, including gastrointestinal events, myalgia or muscular pain, hepatic dysfunction, headache, and fatigue, but does not specifically highlight a significant increase in CK levels. In contrast, statins are known to cause muscle-related side effects, including elevated CK levels, in a significant proportion of patients, as mentioned in the same study. The difference in mechanism of action between ezetimibe and statins explains why ezetimibe is less likely to cause muscle damage and subsequent elevations in CK levels.

When considering the use of ezetimibe, either as an alternative or add-on therapy to statins, it is essential to weigh the benefits of its use against the potential risks. The study 1 provides evidence on the efficacy and safety of ezetimibe in combination with statins, showing that it can effectively lower LDL-C levels and reduce the risk of cardiovascular events without significantly increasing the risk of muscle symptoms or elevated CK levels. However, as with any medication, rare cases of muscle pain or weakness can occur, and patients should be monitored and advised to report any muscle symptoms to their healthcare provider.

Key points to consider:

• Ezetimibe works differently from statins, blocking cholesterol absorption in the intestine rather than acting in the liver.
• Ezetimibe is less likely to cause muscle damage and elevated CK levels compared to statins.
• The combination of ezetimibe with statins can be effective in lowering LDL-C levels and reducing cardiovascular risk without significantly increasing muscle-related side effects.
• Patients should be monitored for muscle symptoms, and their medication regimen should be adjusted as necessary to minimize risks and maximize benefits, as supported by studies such as 1 and 1.

From the FDA Drug Label

Ezetimibe tablets may cause myopathy [muscle pain, tenderness, or weakness associated with elevated creatine kinase (CK)] and rhabdomyolysis [see Adverse Reactions (6. 1)]. In post-marketing reports, most patients who developed rhabdomyolysis were taking a statin or other agents known to be associated with an increased risk of rhabdomyolysis, such as fibrates.

Ezetimibe may increase creatine kinase (CK) levels, similar to statins, as it may cause myopathy and rhabdomyolysis. However, the label does not provide a direct comparison of the magnitude of CK level increases between ezetimibe and statins.

• Key points:
  • Ezetimibe may cause myopathy and rhabdomyolysis
  • Elevated CK levels are associated with myopathy
  • Most cases of rhabdomyolysis occurred in patients taking ezetimibe with a statin or other agents known to increase the risk of rhabdomyolysis 2 2

From the Research

Ezetimibe and Creatine Kinase Levels

• Ezetimibe, a cholesterol absorption inhibitor, has been reported to cause elevation of creatine kinase (CK) levels in some cases, similar to statins (HMG-CoA reductase inhibitors) 3.
• However, the pathogenesis of muscle toxicity associated with ezetimibe is not fully understood, and it is unclear whether ezetimibe increases CK levels to the same extent as statins.
• A study found that ezetimibe monotherapy was associated with reversible elevation of CK levels in two patients who had previously experienced intolerance to other lipid-lowering agents 3.
• In contrast, another study found that ezetimibe did not increase CK levels in a patient with chronic kidney disease and statin-intolerant dyslipidemia, and actually reduced serum levels of low-density lipoprotein cholesterol and triglyceride 4.
• A comparative study of ezetimibe added to statin versus statin titration in chronic kidney disease patients found that the combination of ezetimibe and statin was associated with fewer adverse effects, including skeletal muscle complaints and elevated CK levels, compared to statin uptitration alone 5.

Comparison with Statins

• The IMPROVE-IT trial found that the addition of ezetimibe to simvastatin resulted in a greater reduction in cardiovascular events compared to simvastatin alone, particularly in patients with reduced kidney function 6.
• A retrospective study found that ezetimibe was effective and safe in combination with statin therapy in kidney transplant patients with uncontrolled hypercholesterolemia, with no significant changes in CK levels or other safety parameters 7.
• Overall, the evidence suggests that ezetimibe may not increase CK levels to the same extent as statins, and may be a useful alternative or addition to statin therapy in certain patient populations, such as those with chronic kidney disease or statin intolerance 3, 4, 5, 6, 7.