The Effects of Plant Stanol Ester in Different Subject Groups

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Abstract

Different food products enriched with plant stanol esters have proved effective and safe as a dietary hypocholesterolaemic tool in about 60 published clinical studies during 15 years on the market. In addition to lowering low-density lipoprotein (LDL) cholesterol by 10% with a dose of 2g/day, plant stanol effectively reduces serum plant sterols and also, in some studies, serum triglycerides. It has been shown to be an effective dietary hypocholesterolaemic agent in adults and children with primary hypercholesterolaemia, in familial hypercholesterolaemia, in coronary subjects and in type 1 and type 2 diabetes. Plant stanol ester can be combined with statin to obtain more powerful serum total and LDL cholesterol reduction. This combination therapy inhibits both cholesterol synthesis and absorption. Plant stanol ester reduced the C-reactive protein (CRP) level in recent studies and, in contrast to ezetimibe, it does not change the LDL particle size. Plant stanol ester consumption tends to reduce the plant sterol contents of arterial wall, and in some, but not all, studies it improves endothelial function, a surrogate marker of pre-clinical atherosclerosis.

Support: The publication of this article was funded by Raisio plc. The views and opnions expressed are those of the authors and not necessarily of Raisio plc.

Disclosure
The authors have no conflicts of interest to declare.
Correspondence
Helena Gylling, Department of Clinical Nutrition, University of Eastern Finland, PO Box 1627, 70211 Kuopio, Finland. E: helena.gylling@uef.fi
Received date
12 August 2010
Accepted date
06 September 2010
DOI
http://dx.doi.org/10.15420/ecr.2010.6.3.18

Plant stanols and plant sterols are normal components of plants, and they are present in normal food; approximately 30mg of plant stanols and about 300mg of plant sterols are present in normal daily food. Vegetable oils, especially corn oil, soybean oil, and rapeseed oil, are rich especially in plant sterols, but they also contain small amounts of plant stanols. Plant stanols differ in their chemical structure only slightly from plant sterols by having a saturated delta-5 double bond; however, this small structural difference is enough to make them completely different compounds. The intestinal absorption of plant stanols is very low and varies from 0.04 to 0.1% compared with 0.5– 1.9% of plant sterols.1 As a result of low absorption efficiency, the amount of plant stanols in the human body is small, and their serum and tissue levels are less than 1/10 to 1/50 of those of plant sterols. The serum levels of plant stanols vary in the normal population between 2 and 10μg/dl (0.05–0.3μmol/l), and those of plant sterols between 100 and 800μg/dl (3–21μmol/l). However, the serum levels of both plant stanols and plant sterols are very low compared with the serum cholesterol level of 190mg/dl (5.0mmol/l). When plant stanol-enriched margarine is customarily used, the serum plant stanol concentrations were increased in subjects from 0.2 to 0.7μmol/l (from 8 to 27μg/dl), but serum plant sterols were decreased by 16–23%.2 During customary plant sterol-enriched margarine consumption, the serum plant sterol concentrations were increased from 19 to 30μmol/l (730 to 1158μg/dl) with no change in serum plant stanol values.2 Accordingly, serum plant stanol and plant sterol concentrations are increased during plant stanol- and plant sterol-enriched functional food consumption, but the levels of serum plant stanols remain very low compared with those of plant sterols, and plant stanol consumption decreases not only serum cholesterol but also serum plant sterol levels.
In 1986, it was shown for the first time that plant stanols act as hypocholesterolaemic agents in humans. Free plant stanols at 1.5g/day lowered serum total and low-density lipoprotein (LDL) cholesterol by 10 and 15% from home values in a four-week study.3 Plant stanols inhibit cholesterol absorption, and since the free plant stanols are poorly soluble it was considered that in the intestinal micellar milieu their esterified, more soluble forms might be more effective than the free form. Also, the ester form of plant stanols allows production of good quality food products with effective cholesterol lowering.

The first controlled clinical experiment with plant stanol esters was published in 1991.4 In 1995, the one-year study confirmed significant 10 and 14% reductions in total and LDL cholesterol levels, respectively, with plant stanol ester in margarine in a mildly to moderately hypercholesterolaemic population.5 There were no changes in highdensity lipoprotein (HDL) cholesterol or serum triglyceride levels, and it was well tolerated. Plant stanol ester margarine (Benecol®) was launched the same year. The reason why plant stanols were chosen for Benecol was their low intestinal absorption and low systemic availability. In fact, it turned out that even with very large doses of plant stanol esters of up to 8.8g of plant stanols/day their systemic availability still remained very low and similar to the doses of 2–3g/day of plant stanols.6
To date, about 60 randomised controlled clinical trials with different food products enriched with plant stanol esters have been published in international peer-reviewed journals. In a meta-analysis, 2g/day of plant stanols, mainly in esterified form, lowered LDL cholesterol levels by 10%.7 No side effects have been reported. It was recently shown that the hypocholesterolaemic effect of plant stanol esters can be dose-dependently increased, so that about 9g/day of plant stanols as esters lowered LDL cholesterol levels by 17%.8,9 An additional beneficial effect is that plant stanol esters reduce serum plant sterols up to 60%. This might be of importance, as a recent genome-wide study showed that common variants in the sterol transporter ABCG8 gene and in the blood group ABO locus were strongly associated with serum plant sterol levels and coronary artery disease (CAD).10 The ultimate reason for enrichment of diet with esterified plant stanols is to have maximal dietary cholesterol lowering for the prevention of cardiovascular disease. LDL cholesterol lowering of 10% with 2g of plant stanols has been calculated to reduce coronary events in the long term by about 20%.11 Most of the published clinical studies have been performed in adult subjects with primary mild to moderate hypercholesterolaemia, but plant-stanol-ester-enriched food products have also been shown to be effective and safe in children and adults with familial hypercholesterolaemia. Accordingly, the aim of this article was to focus on the efficacy of plant stanol esters in specific groups, i.e. subjects with CAD, type 1 and 2 diabetes and plant stanol esters combined with statin treatment.

Mechanism of Action

Plant stanol esters interfere with the micellar solubilisation of cholesterol and plant sterols.12,13 This is followed by increased excretion of both cholesterol and plant sterols in faeces,14 and a reduction in the amount of both entering the enterocyte membrane transporters and the enterocytes. Plant stanol esters reduce cholesterol absorption efficiency more in subjects with high absorption.15 Serum cholesterol values are reduced more in subjects with high than in those with low cholesterol absorption16 and more in subjects with a low synthesis–absorption ratio than those with a high synthesis–absorption ratio.17 According to these findings it could be assumed that plant stanol esters are most effective in subjects with high absorption efficiency of cholesterol. Furthermore, to obtain the best efficacy of hypocholesterolaemic treatment, it would theoretically be ideal that subjects with high cholesterol absorption consume plant stanol esters, whereas those with high synthesis are primarily treated with statins. This targeted approach has been succesful in some,16–20 but not all,21 studies.

Coronary Artery Disease and Plant Stanol Esters

Do coronary subjects have a specific type of cholesterol metabolism favouring either the inhibition of cholesterol synthesis or cholesterol absorption? According to the available data, cholesterol metabolism might not be homogeneous in coronary subjects. In middle-aged women with CAD, cholesterol synthesis was lower and cholesterol elimination from the body inefficient compared with controls, despite similar serum cholesterol values.22 Furthermore, the serum plant sterols campesterol and sitosterol were increased23 by about 20% without difference in cholesterol absorption, suggesting that plant sterol metabolism was disrupted in coronary women.24 However, in a subgroup (n=268) of the Scandinavian Simvastatin Survival Study (4S), coronary patients were divided into two groups: a low HDL cholesterol–high serum triglyceride group (HTG); and a group having normal HDL cholesterol and serum triglyceride levels but isolated elevation of LDL cholesterol level (ILDL).25 The number of subjects in each group was almost equal. Serum cholesterol values did not differ between the groups, but subjects with HTG had high synthesis and low absorption of cholesterol assayed with serum non-cholesterol sterols, and features of metabolic syndrome. The subjects with ILDL were high absorbers and had low synthesis of cholesterol.

The hypocholesterolaemic effect of plant stanol esters in coronary subjects has been evaluated in three studies.26–28 In post-menopausal CAD women without hypocholesterolaemic treatment, plant stanol ester in margarine with 3g of plant stanols/day reduced serum total and LDL cholesterol levels by 8 and 15% from the control period (margarine without plant stanols), and by 13 and 20% from baseline home diet.26 LDL cholesterol was reduced in every subject, but most in those with the highest baseline values. Triglyceride content in LDL and HDL significantly decreased, whereas HDL cholesterol was unchanged. Moreover, serum plant sterol levels were decreased about one-third from the baseline values. When the results in CAD women were compared with age-, body mass index (BMI)-, and serum lipid-matched non-coronary women, plant stanol ester consumption was equally effective in both groups.27 In men with CAD and on statin treatment, addition of plant stanol ester margarine (3g of plant stanols/day) reduced LDL cholesterol by 15% and non-HDL cholesterol values by 14% from the statin-only values.28 These studies showed that plant stanol esters were as effective hypocholesterolaemic agents in coronary as in non-coronary subjects,7,29 and the reduction was of similar magnitude as with ezetimibe. Interestingly, plant stanol ester consumption reduced C-reactive protein (CRP) values from 2.96mg/l to 1.72mg/l.28 A similar favourable effect of plant stanol esters on highly sensitive CRP values has been confirmed recently in a large population of non-coronary subjects.30 This finding is an additional beneficial effect of plant stanol ester consumption in terms of the prevention or regression of atherosclerosis. There are, however, no end-point studies with plant stanol ester, free plant stanol, free plant sterol or plant sterol ester consumption.

Vascular Health and Plant Stanol Esters

The possible effects of plant stanol esters on vascular health using the surrogate markers of the risk of cardiovascular events (intima-media thickness, flow-mediated dilatation, arterial stiffness) have been evaluated in non-coronary subjects in short- and long-term studies, with controversial results. In children with familial hypercholesterolaemia,31 in a one-year study in mildly hypercholesterolaemic adults,32 and in type 1 diabetes,33 plant stanol esters had no effect on vascular properties despite cholesterol lowering.

On the other hand, plant stanol ester consumption for two years or more seemed to be associated with beneficial changes in carotid artery compliance,34 and three-month consumption of plant stanol esters improved carotid artery compliance and flow-mediated dilatation in subjects with initially reduced respective values.35 Accordingly, it seems evident that sufficiently long treatment is needed for beneficial effects in the vascular wall, but it is also evident that plant stanol ester consumption is not harmful to vascular health even in the long term.

Plant Sterols During Plant Stanol Ester Consumption

Epidemiological studies have shown that in some populations on habitual normal diet and without plant sterol supplementation serum plant sterol levels are higher in CAD patients than in controls, but in other studies these results cannot be confirmed. However, the discussion of whether elevated serum plant sterols are harmful to vascular health is not yet closed. Plant sterol consumption in functional foods7 and large-dose statin treatment36 can double serum plant sterol levels. Plant sterols are not present only in serum; they are also distributed with lipoproteins in the tissues. Tissue concentrations, e.g. in carotid artery including atheromatous plaques37 and stenotic aortic valves,38,39 correlate with the serum values, suggesting that the higher the serum plant sterol values, the higher the plant sterol level in vascular wall. However, whether the plant sterols have any pathological role beyond cholesterol in vascular health in humans is not known.
Plant stanol ester consumption decreases not only serum but also tissue plant sterol levels. In subjects with familial hyper-cholesterolaemia, plant stanol ester consumption for four weeks lowered LDL cholesterol by 15% and plant sterols in serum and in red blood cells by 25%, whereas plant sterol supplementation increased plant sterols in serum and red blood cells up to 80%.40 Similarly, plant stanol ester consumption for four weeks pre-operatively decreased the plant sterol contents in carotid arteries in endarterectomised subjects.41 Importantly, plant stanols in arterial wall were not increased during plant stanol ester consumption. Accordingly, in addition to reducing serum total and LDL cholesterol, plant stanol esters reduce the plant sterol levels in serum and tissues.

Type 1 and Type 2 Diabetes

Cholesterol metabolism is perturbed in type 1 diabetes so that cholesterol absorption efficiency is high and synthesis is low;42 therefore, a favourable hypocholesterolaemic effect could be expected with plant stanol esters. In fact, in a small group of subjects with type 1 diabetes with serum total and LDL cholesterol values of about 5.1 and 2.8mmol/l, plant stanol ester consumption for 12 weeks (plant stanols 2g/day) lowered LDL cholesterol 16% from controls.33 There were no changes in HDL cholesterol or serum triglyceride levels. Accordingly, these results suggest that patients with type 1 diabetes may benefit from plant stanol ester consumption.
In type 2 diabetes, cholesterol synthesis is elevated and cholesterol absorption efficiency is low.43 Accordingly, cholesterol absorption inhibition might be less effective in these subjects. In a recent meta-analysis, five clinical studies with plant stanol or plant sterol consumption in patients with type 2 diabetes were tracked;44 plant stanol ester was used in two studies, a mixture of free plant sterols and stanols was used in one study, free plant sterols in one and plant sterol ester in the remaining study. The total number of subjects was 148, and the intervention period ranged from three to 12 weeks. The use of plant stanols and sterols significantly reduced total and LDL cholesterol with a trend towards HDL cholesterol raising. The LDL cholesterol reduction in the meta-analysis was about 12mg/dl. It has been calculated that 1mg/dl reduction in LDL cholesterol level reduces 1% of the relative risk of CAD.45 Accordingly, the results of the meta-analysis suggest that the hypocholesterolaemic effect of plant stanol esters is of clinical significance also in type 2 diabetes.

Statins and Plant Stanol Esters

Statin treatment was shown for the first time by two studies to derease serum levels of synthesis markers and increase those of absorption markers of cholesterol.46,47 Subsequently, addition of plant stanol ester margarine to the food of patients on statin treatment was shown to further lower serum cholesterol by over 16% and reduce increased plant sterols to relatively low levels.26 At that time no adverse effects of slightly increased serum plant sterols were believed to be caused in terms of prevention of atheromatous vascular events, especially as LDL cholesterol was markedly decreased.

However, in 1998, a subgroup analysis of the 4S population showed that during the five-year simvastatin treatment period, the new coronary event rate was significantly reduced only in the group with low baseline cholesterol absorption (low serum plant sterols) but, if anything, increased in those with high absorption.19 It was suggested that subjects with high baseline absorption and low synthesis of cholesterol were not satisfactorily responding to statins and should be treated with combined cholesterol synthesis and absorption inhibitors, e.g. statin combined with plant stanol ester. A closer analysis showed that the higher the baseline plant sterol concentration the higher their increase during the long-term statin treatment.20 This means that high baseline cholesterol absorbers can increase their plant sterol levels in proportion to the type and dose of statin and to the length of the treatment. Similar findings were observed also in another long-term treatment with different statins of varying doses, showing during its short initial period tendencies to decreased serum plant sterol ratios followed by their gradual increase during continuance of the treatment.48 In an additional study, a large dose of effective statin in men with type 2 diabetes reduced serum cholesterol and plant sterol ratios initially in most lipoprotein fractions, followed by gradual increase of plant sterols with simultaneous increase of faecal cholesterol elimination and intestinal sterol absorption.36
In view of these long-term observations of statin treatment, it is interesting to note that a single dose of statin lowers serum plant sterols transiently during the first 12 hours by up to 20%.49 This means that owing to rapid equilibration of lipoprotein plant sterols with those from red cells40 and endothelial cells,37,38 a relatively large amount of blood plant sterols rapidly disappears from circulation. Increased hepatic uptake of circulating lipoproteins, mainly LDL, might augment the plant sterol levels. During continuing statin treatment, serum plant sterol levels return to initial or even increased levels, especially in ratio to serum cholesterol. Even though intestinal plant sterol absorption could be increased, enhanced synthesis of LDL cholesterol could return hepatic plant sterols back to the serum and even reach a higher level in long-term statin treatment. Long-term (85 weeks) stanol ester treatment in current statin-treated subjects reduced LDL cholesterol by 13.1%, but had no effect on oxysterols or a bile acid synthesis marker.50

It is interesting to note that in statin-treated patients, ezetimibe plus plant sterols reduced LDL cholesterol more than ezetimibe or plant sterols alone; it was concluded that the combination of the two may have a benefit for coronary patients on statins not reaching the LDL cholesterol goal.51 A closer analysis of LDL on ezetimibe with or without simvastatin revealed increased atherogenic small dense LDL particles,52 a finding that could explain the lack of effect of further cholesterol lowering on changes in intima-media thickness by the combination of ezetimibe with statin.53 This finding would mean that a combination of plant stanol esters with statins would be beneficial for additional lowering of cholesterol in coronary patients, since plant stanol esters do not change LDL particle size. The longest annually reported follow-up of serum plant sterols and plant stanol ester treatment, partly with statins, in a single patient has been around 15 years, showing marked serum cholesterol reduction and around 45% reduction of serum campesterol and sitosterol levels, and an increase of serum sitostanol concentration only to 30μg/dl during the treatment period.54 Current sterol values after about 21 years of treatment have remained quite similar, but no stanol ester-related side effects have been observed.
Stanol esters have no systematic effect on serum triglycerides, even though some reduction has been recorded, especially in those with increased baseline triglyceride values.55 Meta-analysis of the triglycerides in randomised studies of combined statin plus plant sterol/stanol-treated versus resin-treated subjects (n=306) revealed significant reductions of total and LDL cholesterol, but no consistent change in triglyceride or HDL cholesterol levels.56 In another study, six postprandial day-long triglyceride measurements over three days during statin versus statin plus plant stanol treatment showed no consistent postprandial change in areas under the day-long curve of serum triglycerides. LDL cholesterol had significantly reduced by 15.6% in the combined treatment versus 7.7% in the statin group.57 Accordingly, the effect of plant stanol esters on serum triglyceride levels seems controversial at present.

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