From the Maastricht meeting to the European Atherosclerosis Society Consensus on phytosterols/phytostanols: What is new of an old story?

The impact of diet on cardiovascular disease (CVD) risk is well established. Since 1966, when the Seven Countries Study was published [], numerous studies have been carried out looking at the effects of dietary components and/or dietary patterns on risk factors or even end points of CVD. Dietary Randomized Controlled Trials with hard outcomes are limited, and most of them focus on dietary patterns. The vast majority investigates the effects of dietary components on CVD risk, and has as main target the decrease in LDL-cholesterol (LDL-C) levels. Considering that the success of a dietary modification depends strongly on adherence, a nutraceutical industry was developed seeking easier solutions to an increasingly alarming health problem, especially in the westernized societies.

Phytosterols and phytostanols are dietary components which are known to have a hypocholesterolemic effect. The story of this hypocholesterolemic effect is not really new. Ancel Keys and his co-workers in a very interesting review, published in 1974, quoted among others: “The literature on the effect of phytosterol in man subsisting on natural foods is in agreement that the lowest amount that can be hoped to produce a discernible reduction in serum cholesterol is approximately 6 to 10 g daily. With a formula diet in a trial of only 8 days, the lowest effective dose was reported to be 870 mg daily. However, in that experiment, daily doses of 5500 and 8000 mg produced cholesterol declines of only 25 and 29 mg/dl. The brevity of the trial and the absence of natural foodstuffs in it, makes it impossible to be guided by that report as opposed to 19 other studies that 10 or more times that dosage is needed. Note that 870 mg of phytosterols correspond roughly to the amount in 100 g of corn oil, the richest source of phytosterols among common food fats.” This quote, which is almost 40 years old, indicated that although an effect could be found, it would be almost impossible for this effect to be reached by a simple dietary modification [].

The vast majority of research in the effects of sterols/stanols on LDL-C levels is relatively recent. The first expert meeting on the efficacy and safety of plant sterols/stanols was held in Stresa, Italy in 2001. As a result, a meta-analysis was published which included 41 placebo-controlled trials []. Consensus was reached stating that an intake of 2 g/d of plant sterols or plant stanols lowers serum LDL-C levels up to 10%, with little additional benefit at higher intakes. The second expert meeting was held in Maastricht, the Netherlands in November 2011 where 60 academic and industrial experts discussed topics related to the health effects of plant sterols and plant stanols. Among their conclusions was that at doses up to 3 g/d, plant sterols and plant stanols have equal LDL-C lowering efficacy, with an average reduction of approximately 10%, in a wide range of populations including type 2 diabetics, metabolic syndrome patients, and familial hypercholesterolemics. In this meeting, it was the first time that a potentially modest lowering effect on fasting triglyceride concentrations was discussed [].

In a previous issue of the Journal, The European Atherosclerosis Society (EAS) International Consensus Panel recommendations are published on plant sterol and plant stanol biology, and their effects on various aspects of CVD []. This paper together with the outcomes of the Maastricht meeting, gives a global view on the effects of phytosterols/stanols on CVD and also helps the physician and the dietitian to give valuable advice to their patients.

In particular, in this paper, and in agreement with the recommendations of other panels, it is suggested that at doses of plant sterols/stanols of 2 g/d a similar lowering effect of LDL can be expected, and it is also concluded that it remains open whether there is a position for plant sterol and/or plant stanol intakes to be raised higher than those currently recommended in prevention strategies for the general population. The Panel also suggested that sterols/stanols supplementation could be considered in children (from the age of 6 years) with familial hypercholesterolemia, as an adjunct to lifestyle advice and potential pharmacotherapy, although more long term studies which should include safety issues are necessary to be carried out.

As with the outcomes of the Maastricht meeting, the EAS Consensus Panel reviewed the data on the effects of phytosterols/phytostanols on triglyceride levels. The panel concluded that the available data suggest that triglyceride levels can be reduced by 6–20% at intakes of 1.5 to 2 g/d of plant sterol/stanol, although a pooled analysis showed only a modest reduction in plasma triglycerides of 6% and 4% for recommended intakes of plant sterols (1.6–2.5 g/d) or plant stanols (2 g/d), respectively. Moreover, a relationship between baseline triglyceride levels and the magnitude of this effect was also observed. Clearly, there is a need for further studies on the effects of sterols/stanols on triglyceride levels in fasting and/or postprandial periods. If the current findings are confirmed, or if the magnitude of effect is found to be more pronounced in moderate hypertriglyceridemic patients, then the actual effect of these compounds on the total CVD risk will be significantly altered.

The Panel also reviewed the data regarding accumulation of plant sterols/stanols in the arterial wall. In the literature, there is some reluctance by researchers and/or physicians to suggest the consumption of phytosterols/phytostanols due to this potential side-effect. However, as was noted in a recent meta-analysis which included 17 studies, no significant associations of circulating campesterol and sitosterol with vascular disease was shown over a range of circulating plant sterol concentrations, although the possibility of an accumulation of plant sterols/stanols in vascular cells as a consequence of an increase in their circulating concentrations could not be excluded. It was also acknowledged that retrospective/case-control and prospective/cohort studies do not provide the highest level of evidence in defining causality, and since placebo-controlled trials with these endpoints are lacking, the panel suggested that Mendelian randomization studies should be used and these available data do not provide a scientific basis to discourage the use of plant sterol- or plant stanol-containing functional foods. In addition, in animal models of atherosclerosis, protective effects were observed despite increases (up to 10-fold) in plasma plant sterol/stanol concentrations. Such effects included reduction in arterial lipid accumulation, and inhibition of lesion formation and progression. Moreover, regression of existing lesions correlated with the cholesterol-lowering action of plant sterols/stanols. Along these lines, it is of interest that in another paper published recently in this journal, in phytosterol-fed mice, although plasma phytosterol levels were higher than in controls, firstly the arterial wall phytosterol concentrations did not differ between groups and secondly the atherosclerotic lesion area in the phytosterol group was smaller than that in controls [].

Where do all these leave us? If normal plasma phytosterol levels, which are known to be about 0.3–1.0 mg/dL, and normal plasma cholesterol levels around 200 mg/dL, then a 10% reduction in cholesterol levels would mean approximately 20 mg/dL, which clinically would be much more significant than even a proportional increase in plasma phytosterol concentrations. In addition, in patients with phytosterolemia, who may develop premature atherosclerosis, plasma phytosterol levels are in the range of 20–70 mg/dL, which are well above the normal concentrations. Therefore, especially in the primary prevention and for patients with mildly to moderately increased plasma cholesterol levels, phytosterols/phytostanols have a place in treatment, since their benefits outweigh substantially the risks. We shouldn't though overlook the fact that this should be part of a dietary modification plan, and consequently the rest of the dietary behavior of the patient must be taken into account. If therefore phytosterols/phytostanols could lead to a 10–15% reduction in LDL-C levels and possibly to a lesser extent a reduction in triglycerides, this would affect risk reduction, but the impact will be even greater if a complete dietary modification is also achieved and maintained.

The EAS Consensus Panel also considered phytosterol/phytostanol supplementations as part of a combination therapy. It is suggested that dietary plant sterols/stanols could induce an incremental decrease in LDL-C levels of 10–15% when added on top of statin therapy, which is superior to that (6%) obtained by doubling the statin dose. Moreover, in vivo studies of LDL-apoB kinetics in patients with type 2 diabetes mellitus indicated that the additive effects on LDL reduction when stanols were added to statins resulted from decreased production of LDL. Clinical studies also showed a trend for an additive effect on LDL-C levels when foods enriched with plant sterols/stanols were consumed with a fibrate. Finally, since n-3 fatty acids have a small effect on cholesterol metabolism and mainly influence triglyceride levels, consumption of plant sterols/stanols and n-3 fatty acids may exert a complementary beneficial effect on the lipid profile. However, research in this area of combination therapy, although promising, is still limited, and more studies are needed.

Finally, the EAS Consensus Panel also recognized that there is a lack of randomized trials on CVD prevention and this limitation should be taken into account by the physician. However, it was also recognized that large-scale outcome trials of food products with added plant sterols for CVD prevention in the setting of low to intermediate risk may not be practically feasible, mainly due to the very large number of subjects, which was estimated to be >50,000 in order to achieve adequate power. Therefore, it could be argued that as with other dietary factors, we could rely on the evidence of risk factor modification to suggest potential benefits, and not dismiss these products solely from the fact that clinical trials and/or prospective studies with end points are lacking.

In conclusion, the EAS Consensus Panel gives a very balanced interpretation of the current literature. For the treatment of hypercholesterolemia, recommending sterols/stanols consumption can be an option even in combination with statins. However, it must be re-emphasized that the inclusion of these substances in the treatment should not stand alone. Whole grains, fruits and vegetables, olive oil, legumes must be cornerstones of the dietary modification as well as the decrease in animal products and especially ready-to-eat full fat meals.