Therapy and clinical trials: plant sterols and stanols in management of hypercholesterolemia: where are we now?

摘要

The mechanism of cholesterol absorption has remained an enigma until relatively recently. The discovery of ezetimibeas a potent and selective inhibitor of cholesterol absorption has provided new insights in the regulation of cholesterol absorption. It is the protein Niemann-Pick G1 like 1(NPC1L1) in the brush border epithelium of the proximal intestine which is the putative 'sterol permease' involved in cholesterol transport . ABCG5 and ABCG8 are two separate ATP-binding cassette proteins involved in plant sterol exportation into the bile and intestinal lumen respectively , thus preventing their absorption under normal circumstances. These findings have enhanced our current understanding of cholesterol and related sterol absorption and the effect of dietary and drug intervention in management of hypercholesterolemia.The use of phytosterols (plant sterols and stanols) as a mechanism of reducing serum cholesterol has evolved only recently though their effect has been known for several decades . Both havestructural similarity with cholesterol. The difference lies with sterols having a different side chain and stanols lacking the DELTA5 bond in the beta-ring [4~(..)]. They are also less efficiently absorbed than cholesterol (< 0.5% for sterols and 0.05% for stanols). This limiting factor was the main stimulus to develop more lipid soluble stanol esters with long chain fatty acids to improve bioavailability . The mechanism of action of phytosterols is primarily through competitive inhibition of the micellar solubilization and hence intestinal absorption of both dietary and biliary cholesterol . Increased LDL receptor expression in response to decreased exogenous cholesterol has also been noted. Moreover stanols may have a long-lasting effect on cellular cholesterol metabolism in the intestinal enterocytes .The cholesterol reducing property of sterols/stanols has led to numerous studies in the past decade. They havebeen found to reduce total cholesterol, LDL-cholesterol and non-HDL cholesterol without any significant effect on HDL cholesterol or triglyceride [4~(..)]. Reduction in LDL-cholesterol is 10-14% in various studies, which is roughly equivalent to twice doubling the dose of statins. Further benefit has been noted with stanol esters in association with increased dietary polyunsaturated fatty acid. The optimum LDL-cholesterol lowering effect is achieved at approximately 2 g/day and there is no justification for using less than 1 g or more than 2 g daily [4~(..)]. Usually two to three divided doses with meals have been used but persistence of a similar effect with a single daily dose suggests a long-lasting effect on the intestinal mucosa [4~(..)]. There is not much difference between the various sources used but the difference is mainly driven by market forces. Usually the food vehicle used has relatively higher fat content (margarine, butter, mayonnaise) but a few recent studies have focussed on low fat containing food vehicles with similar efficacy .