Effects of MK-733 on plasma lipid and lipoprotein levels in subjects with hypercholesterolaemia.

MK-733, which is a competitive inhibitor of the rate-limiting step in cholesterol biosynthesis, or a matching placebo was administered to 30 subjects with primary hypercholesterolaemia (who were already receiving dietary treatment) over a period of four weeks in a double-blind trial. Twenty-one subjects manifested heterozygous familial hypercholesterolaemia and nine subjects had polygenic hypercholesterolaemia. Five subjects received placebo, 15 subjects a low dose of MK-733 (2.5-10 mg/day) and 10 subjects received a high dose of MK-733 (20-80 mg/day). Plasma cholesterol levels in subjects who were receiving MK-733 declined significantly and in a dose-dependent fashion (31% reduction in plasma cholesterol levels with a high dose, 19% reduction with a low dose). Eight of 10 subjects who were receiving a high dose of MK-733 achieved better than a 30% reduction in plasma cholesterol levels after four weeks of treatment. The response was independent of the presence or absence of familial hypercholesterolaemia. High-density lipoprotein cholesterol levels did not change significantly, but there was a suggestive, dose-dependent reduction in plasma triglyceride levels after four weeks of treatment. MK-733 was well-tolerated, appeared to be safe, and may ultimately become an important drug in the management of more severe grades of hypercholesterolaemia.