Ezetimibe: new preparation. A cholesterol-lowering drug with no clinical advantage.

(1) Simvastatin and pravastatin are the drugs of choice for secondary or primary prevention of cardiovascular events in patients with hypercholesterolaemia. Both these statins have proven clinical efficacy. If statin therapy is inadequate, the dose can be increased or a drug combination can be tried, while keeping a lookout for adverse effects. (2) Ezetimibe is a cholesterol-lowering drug that is said to inhibit intestinal absorption of cholesterol and related phytosterols, while not affecting the uptake of other nutrients (unlike resins). (3) The clinical evaluation dossier contains no data from trials with relevant morbidity or mortality endpoints. Primary and secondary prevention were not studied separately. (4) In patients with hypercholesterolaemia, two placebo-controlled trials show that ezetimibe reduces total cholesterol concentration (by about 13%), and LDL-cholesterol (by about 18%). Its effects on HDL-cholesterol and triglyceride levels are at best moderate. It is not known whether these effects reduce mortality or prevent cardiovascular events. (5) Four trials tested initial combination therapy with a statin plus ezetimibe, in comparison with statin alone and ezetimibe alone. They showed an additive effect of the two drugs on LDL-cholesterol levels. Ezetimibe alone was no better than statin monotherapy. (6) A trial in patients who did not respond adequately to statin monotherapy showed that adding ezetimibe increased the number of patients whose LDL cholesterol level fell to a predetermined cutoff point. But the clinical relevance of this result is unknown. Two other trials have shown that, in this setting, adding ezetimibe to simvastatin or to atorvastatin increased the number of patients who reached the LDL-cholesterol cutoff relative to continued statin monotherapy at a higher dose. (7) In homozygous familial hypercholesterolaemia, high-dose statin and ezetimibe combination therapy reduced the LDL-cholesterol more effectively than high-dose statin alone. It is not known whether adding ezetimibe is more effective than LDL apheresis alone. (8) In homozygous familial sitosterolaemia, a very rare disorder due to increased absorption of dietary cholesterol and phytosterols, a placebo-controlled trial showed that ezetimibe had no significant impact on the absolute sitosterol value. (9) Comparative trials reported no major adverse effects associated with ezetimibe, but their duration (maximum three months) is too short to rule out long-term adverse effects. Initial pharmacovigilance reports cases of muscular and hepatic adverse effects. (10) In practice, ezetimibe has discernible effects in the laboratory. But the absence of data based on clinical endpoints and trials versus other cholesterol-lowering drugs with proven clinical benefits, together with the lack of information on possible long-term adverse effects, means ezetimibe must be evaluated more thoroughly before it can be recommended for routine use.