Ezetimibe

Ezetimibe is the first of a new class of drugs that selectively inhibit cholesterol absorbtion in the small intestine and reduce plasma LDL cholesterol. Used alone, it reduces LDL cholesterol by 15-20%.

Much is made of the potential for combination therapy with ezetimibe - its action lowering sterol absorption should be synergistic in efforts to lower LDL with that of statins, operating via the inhibition of cholesterol synthesis. Low doses of ezetimibe and simvastatin produce greater improvements in lipid profile than monotherapy alone - for example, simvastatin 10 mg and ezetimibe 10 mg reduce LDL cholesterol by 44% (equivalent to simvastatin 80 mg monotherapy).¹ As targets for LDL cholesterol become lower, dual therapy may offer a way forward.²

Inegy® is a fixed dose combination containing ezetimibe and simvastatin. It offers convenience but is typically more expensive than co-administration of the two drugs.³

Ezetimibe is a relatively new drug, and was licensed on the basis of its cholesterol-lowering powers. It has no proven efficacy for the primary or secondary prevention of CHD:

• No large-scale RCTs looking at clinical outcomes and proving efficacy in preventing the complications of atherosclerosis have been published yet. Several are in progress, involving high risk populations (familial hypercholesterolaemia, chronic renal disease and acute coronary syndrome) and their results should be published in the next few years. The results of the ENHANCE trial (Effect of Combination Ezetimibe and High-Dose Simvastatin vs Simvastatin Alone on the Atherosclerotic Process in Patients with Heterozygous Familial HHypercholesterolaemia) were controversially delayed - and showed no difference in the thickening of the carotid artery intima in those with heterozygous familial hypercholesterolaemia in those taking simvastatin (80 mg) and ezetimibe (10 mg) compared to simvastatin (80 mg) alone.^4,5 The value of studies using surrogate endpoints, rather than those based on endpoints with clinical utility, has again been challenged.
• No long-term safety data is available yet.

• Primary hypercholesterolaemia (as above)
  Note, the FDA in the US, has licensed ezetimibe in combination with finofibrate, again as adjunctive therapy. Its use with fibrates is not currently recommended in Europe.
• Homozygous familial hypercholesterolaemia - co administered with statin
• Homozygous sitosterolaemia - adjunctive therapy

• Hypersensitivity
• Pregnancy and breast feeding
• Moderate to severe liver impairment - avoid if unexplained or persistent rise in AST

Monotherapy

Usually well-tolerated. Common side-effects:

• Headache
• Abdominal pain

Rare:

• Thrombocytopenia
• Hypersensitivity
• Pancreatitis, hepatitis, cholelithiasis, cholecystitis
• Arthralgia, myalgia, myopathy, rhabdomyolysis
• Raised creatinine kinase

With statin

(similar to statin sole administration)

• Headache and fatigue
• GI disturbance
• Myalgia
• Elevation of transaminases to >3x upper limit of normal - approx. 2%
• Elevation of creatine kinase to >10x upper limit of normal - 0.3%

• When co-administered with a statin, refer to the Summary of Product Characteristics (SPC) for that particular statin.
• Do not prescribe Inegy® concurrently to other statin therapy.
• When co-administering ezetimibe with a statin, LFTs are advised prior to initiation of therapy and at regular intervals thereafter.
• There are very rare reports of rhabdomyolysis with monotherapy (case reports suggest a higher risk in those who have developed problems with other lipid lowering agents⁸) and ezetimibe is most frequently used with agents that are associated with an increased risk of rhabdomyolysis: all patients should be advised of the risk of myopathy and told to report promptly any unexplained muscle tenderness or weakness.

• Hypersensitivity or intolerance
• Clinical suspicion and/or rise in creatinine kinase levels to more than 10 times upper limit of normal should lead to the drug being stopped immediately.