Cholesterol lowering agent - ezetimibe

Cholesterol lowering is big business these days, with statins firmly established at the heart of antilipidaemic drug regimens. But many patients with high risk factors for coronary heart disease do not comply with their recommended treatments, and up to a third of treated patients are believed to fail to reach their low density lipoprotein (LDL) cholesterol target.

Statins inhibit the enzyme HMG-CoA reductase, thus interfering with the biochemical pathway for the synthesis of cholesterol. Another strategy is the direct targeting of the absorption of cholesterol, and Schering Plough, along with Merck & Co, is developing the drug ezetimibe, which acts as a selective cholesterol absorption inhibitor, both as monotherapy and in combination with statins. Ezetimibe, originally referred to as SCH 58235, selectively prevents the intestinal uptake of both dietary and biliary cholesterol, thus reducing plasma levels of LDL cholesterol.¹

Data from two multicentre placebo-controlled double blind, randomised, parallel group 12 week studies of the use of ezetimibe have been pooled to better evaluate the drug's effect on lipid parameters in patients with primary hypercholesterolaemia.² In the first study, patients were given 0.25, 1, 5 or 10mg ezetimibe, or placebo, once daily before the morning meal. Patients in the second study received the same doses, only at bedtime. A total of 432 patients were included in the analysis, and the 5 and 10mg doses of ezetimibe gave significant reductions of LDL cholesterol, of 15.7% and 18.5% respectively. High density lipoprotein cholesterol increased. Nearly 68% of patients on the higher dose achieved at least a 1% reduction in plasma LDL cholesterol. The drug was well tolerated, and the adverse event profile of those taking the active was similar to the placebo group.

In a further trial, patients with homozygous familial hypercholesterolaemia were treated with ezetimibe alone, or ezetimibe in combination with various doses of either atorvastatin or simvastatin. High doses of statin in combination with ezetimibe reduced LDL cholesterol by an additional 20.5% compared with the group given statin alone.³ This trial indicates that the combination of drugs gives substantially better results in these high risk patients than the statin alone. The two companies have filed an NDA for ezetimibe's use both as monotherapy and in combination, and they hope the drug will be on the market by 2003.