Reduction of Biliary Cholesterol Saturation by Inhibition of Cholesterol Synthesis: New Therapeutic Consequences?

Abstract

Large epidemiological studies have clearly demonstrated that hypercholesterolemia is a major risk factor for coronary heart disease. Dietary and/or drug treatment to reduce elevated serum cholesterol reduces the incidence of cardiac events. At least two placebo-controlled prospective studies revealed a reduction in the incidence of cardiac events [1, 2]. Drug treatment of hyperlipoproteinemia also influences biliary lipid metabolism; for example, in the Coronary Drug Project [3] and the World Health Organization trial [4], treatment of hyperlipoproteinemia was associated with an increased incidence of gallstone formation and cholecystectomies. This side effect of clofibrate had been predicted by measurement of biliary cholesterol output [5]. During treatment with clofibrate the output of biliary cholesterol was higher than without drug treatment. This change in cholesterol secretion was followed by an increase in biliary cholesterol saturation. Other fibric acid derivatives also increase biliary cholesterol saturation by elevation of hepatic output of cholesterol [6–8]. In addition, all fibric acid derivatives studied so far diminished bile acid synthesis, and at least one analogue also decreased hepatic bile acid output [8]. Although fibric acid derivatives are very safe drugs, and at least one derivative reduces the event of cardiac disease [2], the formation of gallstones may be a possible side effect. This is especially a problem in subjects with a higher risk for gallstone formation.