Effect of long term simvastatin administration as an adjunct to ursodeoxycholic acid: evidence for a synergistic effect on biliary bile acid composition but not on serum lipids in humans

Abstract

Background-Stimulated bile acid synthesis preferentially utilises newly synthesised cholesterol, raising the posssiblity that combination of simvastatin (an inhibitor of cholesterol synthesis) with ursodeoxycholic acid (UDCA; a stimulator of bile acid synthesis) may result in reduced bile acid synthesis and greater enrichment of the pool with UDCA than that achieved with UDCA treatment alone. Aims-To investigate the eVect of simvastatin and UDCA given alone and in combination on serum and biliary lipid and biliary bile acid composition. Methods-Eighteen patients with primary non-familial hypercholesterolaemia were studied during treatment with simvastatin 20 mg/day, UDCA 10 mg/kg/day, and a combination of the two drugs. Each regimen was given in random order for three months following a three month lead in period. Results-Simvastatin significantly reduced serum low density lipoprotein (LDL) cholesterol but biliary cholesterol concentration remained unchanged. Combination of the two drugs had no synergistic eVect on serum cholesterol concentration, but significantly increased the proportion of UDCA in the bile acid pool from 35% during UDCA to 48% during combination treatment (p<0.04). Conclusions-Results showed that: (1) simvastatin reduces serum LDL cholesterol but has no eVect on biliary cholesterol concentration, supporting the concept that newly synthesised cholesterol is not the preferential source for biliary cholesterol; and (2) combination of simvastatin with UDCA has the predicted eVect of enhancing the proportion of UDCA in the pool. This eVect may be of benefit in the treatment of cholestatic liver diseases. (Gut 1999;44:552-556)

Effects of combined treatment with pravastatin and ursodeoxycholic acid on hepatic cholesterol metabolism

“…[10], and Lanzarotto et al . [13] have shown that the addition of HMG CoA‐reductase inhibitors, lovastatin or simvastatin, to UDCA results in further reduction of cholesterol saturation: from 80% to 70% in healthy subjects and from 87% to 75% and 83% to 54% in patients with hypercholesterolaemia. The reduction of cholesterol saturation during treatment with UDCA was somewhat less pronounced in studies by Logan and Duane, Mazzella et al ., and Lanzarotto et al .…”

“…When cholesterol synthesis inhibitors (statins) were introduced as plasma lipid lowering agents in the 1980s it was hoped that this class of drugs would also result in dissolution of gallstones. Several studies have shown that the effect of statins on cholesterol saturation is limited [6–13]. With few exceptions, treatment with statins has not resulted in dissolution of cholesterol gallstones [12].…”

Statin pretreatment inhibits the lipopolysaccharide‐induced epithelial‐mesenchymal transition via the downregulation of toll‐like receptor 4 and nuclear factor‐κB in human biliary epithelial cells

“…It has been shown that statins, including simvastatin, show pleiotropic effects including anti‐inflammatory, antioxidant, and anti‐fibrotic effects as well as the ability to lower lipid levels. The anti‐fibrotic effects were demonstrated in non‐alcoholic steatohepatitis animal models by inhibition of HSC proliferation, induction of HSC senescence, suppression of collagen protein synthesis, and eventually reduction of hepatic fibrosis or carcinogenesis . The anti‐fibrotic function was demonstrated in lens epithelial cells and kidney tubular epithelial cells.…”

Scheme for Combined Use of Statins and Ursodeoxycholic Acid in Patients With a High Risk of Cardiovascular Events and Concomitant Non-Alcoholic Fatty Liver Disease: Problems of Practical Application

“…Основанием для сомнений в способности УДХК потенцировать гиполипидемическое действие статинов являются результаты итальянского перекрестного ис-следования, более строгого в методическом отношении, хотя и меньшего по продолжительности и числу участ-ников, чем исследование РАКУРС [25]. В данном ис-следовании не удалось обнаружить преимуществ ком-бинированной терапии (симвастатин 10 мг/сут+УДХК 10 мг/кг/сут) перед монотерапией (симвастатин 10 мг/сут) по влиянию на липиды сыворотки крови [25].…”

“…В данном ис-следовании не удалось обнаружить преимуществ ком-бинированной терапии (симвастатин 10 мг/сут+УДХК 10 мг/кг/сут) перед монотерапией (симвастатин 10 мг/сут) по влиянию на липиды сыворотки крови [25]. Результаты небольшого испанского исследования, в ко-тором такие преимущества были выявлены [26], ма-лоубедительны ввиду серьезных методических нару-шений, допущенных при его проведении [27].…”