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 Adding ezetimibe to ongoing statin therapy provides significant additional lipid-lowering in patients with hypercholesterolaemia, allowing more to reach LDL targets.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. Results from large-scale RCTs looking at efficacy based on clinical end-points are slowly emerging. To date, these have been largely negative:

• 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 Hypercholesterolaemia) 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 The value of studies using surrogate endpoints remains dubious.
• The Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial was the first study of ezetimibe looking at clinical outcomes to be published. It compared simvastatin 40 mg plus ezetimibe 10 mg daily with placebo in people with asymptomatic aortic stenosis. Hyperlipidaemia has been suggested as a risk factor for aortic stenosis. SEAS failed to show good evidence that ezetimibe additionally reduced the risk of cardiovascular events beyond what would be expected of a statin alone.⁵

Safety issues have also emerged: SEAS showed an unexpected 55% increase in new cancers seen in the simvastatin plus ezetimibe group compared with the placebo group (NNH = 26). How to interpret this result?

• The excess risk is based on small numbers of patients so the range of uncertainty around the relative risk is wide.
• Also, the relative risk did not increase significantly with duration of follow-up as might be expected.
• The incident cancers did not cluster into particular, dominant types.
• A further analysis compared the incidence of cancer in the SEAS trial with cancer data from two larger ongoing trials looking at simvastatin and ezetimibe (SHARP and IMPROVE-IT). This failed to show any adverse effect of ezetimibe on rates of cancer.⁶
• Longer follow-up and studies designed to look specifically at cancer risk are needed to more reliably assess the balance of risks and benefits.

With no direct evidence of benefits and some outstanding questions about safety, what is the current position of ezetimibe in the treatment of hyperlipidaemia?

• Primary hypercholesterolaemia - 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

In general, monotherapy is well-tolerated.¹² Common side-effects:

• Headache
• Abdominal pain

Rare:

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

With statin

Side-effect profile and incidence is similar to statin sole administration:¹³

• 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 agents¹⁴) 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 creatine kinase levels to more than 10 times upper limit of normal should lead to the drug being stopped immediately.