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|Commentary on Phytosterol-added Foods|
Focus on lifestyle: EAS Consensus Panel Position Statement on Phytosterol-added Foods
Lifestyle underpins the prevention of cardiovascular disease (CVD). The escalating burden of obesity and diabetes provides impetus for further emphasis on lifestyle preventive measures. Diet is clearly critical; indeed, new data from the Nurses’ Health Study and Health Professionals Follow-up Study provide support for the value of nut consumption in the diet (see below).1
However, are there possibilities for improving the CV risk profile with inclusion of innovative nutritional strategies, so-called functional foods, in the diet? Interest has focused on the role of foods with added plant sterols or plant stanols (often referred to as phytosterols), given the consistent evidence that inclusion of these foods in the diet can lower plasma levels of low-density lipoprotein cholesterol (LDL C) by 8-10%.2-4 The European Atherosclerosis Society (EAS) recently convened a Consensus Panel to appraise evidence for the benefit to risk relationship of foods with added plant sterols and/or plant stanols, as components of a healthy lifestyle, to reduce plasma LDL-C levels, and potentially lower CV risk. The Consensus Statement is now published online in Atherosclerosis,5 with key findings summarised here.
What are plant sterols and plant stanols?
Plant sterols/stanols are natural components of the diet. The main sources of plant sterols are vegetable oils, spreads and margarines, breads, cereals, vegetables and to a lesser extent fruit. The average daily intake of plant sterols is 300 mg; the daily intake of plant stanols is much lower (17-24 mg), mainly from cereals.6 These levels are insufficient for any significant LDL-C lowering effects.
Why do foods with added plant sterols/stanols lower LDL-C?
Plant sterols and plant stanols are metabolised in the small intestine via a 3-step process involving 1) a solubilisation step, essential for entry of sterols into the absorptive cell; 2) uptake into the enterocyte, facilitated by the general sterol transporter protein Niemann-Pick C1-Like1 (NPC1L1); and 3) transport back into the gut lumen via the ATP-binding cassette co-transporters G5 and G8 (ABCG5/ABCG8). The plant sterols and stanols can compete with cholesterol (dietary and biliary) for absorption by the small intestine at each the first two steps; the third step allows for excretion of plant sterols and stanols, thereby maintaining very low levels of each in blood and tissues. Understanding of this process provides the rationale for consumption of foods with added gram quantities of plant sterols/stanols (~2 g/day). At these recommended intakes, there is significant inhibition of cholesterol absorption and lowering of plasma LDL-C levels by 8-10%. Similar lowering of plasma LDL-C levels was observed in trials of children with familial hypercholesterolaemia (FH).7-10
Benefit versus risk considerations
Do plant sterols/stanols accumulate in tissues?
A key issue addressed by the Consensus Panel was the benefit versus risk for inclusion of foods with added gram quantities of plant sterols/stanols in the diet. The available evidence suggests that in healthy human subjects following consumption of these supplemented foods the relative proportions of cholesterol versus sterol/stanol levels are similar in plasma and tissues; levels of sterols/stanols are 500-/10,000-fold lower than those of cholesterol both in plasma and tissues. These data are also consistent with the absence of preferential accumulation or retention in tissues. However, the Panel recognises the need for further study to exclude the possibility that consumption of dietary plant sterols/stanols might result in accumulation in arterial tissues.
Are plant sterols/stanols atherogenic?
The EAS Consensus Panel appraised multiple lines of evidence to address this issue.
In animal models of atherosclerosis, protective effects of supplemental plant sterols and stanols were observed, including reduction in arterial lipid accumulation, and inhibition of lesion formation and progression, despite increases (up to 10-fold) in plasma plant sterol/stanol concentrations (reviewed by Kritchevsky and Chen, 2005).11 However, the Panel does recognise the limitations of such models, in particular the use of high intakes for short duration and recommends the need for studies using physiological intakes. Furthermore, on the basis of limited cell-based data, the Panel cannot exclude the possibility that plant sterols affect the function of cells involved in the development of atherosclerosis, such as endothelial cells, monocytes and macrophages under resting and ’activated‘ conditions in vitro, ex vivo and in vivo, or have significant effects on biochemical surrogate markers of atherosclerosis.
Studies in humans have shown no significant, consistent effects on vascular or endothelial function during short and mid-term plant sterol or plant stanol intake. It is, however, important to bear in mind that the these studies were limited by small numbers of subjects, short duration of intake, and that several studies included individuals at low CV risk with normal vascular function at baseline. Taken together, the data provide no indication that dietary supplementation with plant sterols/stanols is associated with either benefit or harm to vascular function.
Mendelian randomisation studies do not provide evidence of harm associated with circulating plasma levels of plant sterols. Alleles in the ABCG8 gene, which are associated with moderate elevations of circulating plant sterols, showed a positive association with prevalent coronary artery disease.12,13 However, the increase in risk was explained by the association of these ABCG8 variants with increased intestinal cholesterol absorption, as reflected by circulating cholestanol levels, and with increased LDL-C plasma concentration, rather than circulating levels of plant sterols.14,15
Finally, issues have been raised about the possible atherogenicity of plant sterols/stanols given the link between phytosterolaemia, a condition involving severe loss of function mutations in genes coding for the ABCG5/ABCG8 transporters resulting in marked elevation in plasma plant sterol/stanol levels, and premature atherosclerosis. However, it is important to note that manifestation of atherosclerosis in these individuals is variable, and not all patients develop atherosclerosis (E. Bruckert, privileged communication). Indeed, evidence suggests that the presence of premature atherosclerosis in these individuals may depend on whether there is co-existing severe hypercholesterolaemia. Finally, it should be emphasised that this rare genetic disease is beyond the scope of recommended intake of added plant sterols/stanols (2 g/day) as part of a healthy diet for prevention of CVD.
In conclusion, there is a gap in the current evidence-base due to the lack of randomised, controlled clinical trials of sufficient duration with hard end-points. These are needed to definitively evaluate the effects of foods with added plant sterols or plant stanols on CVD outcomes.
Are plant sterols/stanols safe in the long-term?
At the recommended daily intake of 2 g/day, the available evidence does not suggest any adverse effect associated with long-term intake. Rather, evidence from animal and cell studies suggests a protective role of plant sterol intake and risk of certain cancers.16,17 Epidemiological data also associate reduced risk of certain cancers with plant sterol intakes (e.g., stomach and lung cancer).18,19
Modest suppression of plasma carotenoid levels (by 10%) observed during consumption of foods with added plant sterols/stanols can be countered by increasing consumption of fruits and vegetables.20
As mentioned above, long-term randomised, controlled clinical trial data are needed to definitively establish the safety of foods with added plant sterols or plant stanols.
Do plant sterols/stanols have other lipid effects?
There is some evidence that consumption of foods with added plant sterols/stanols (2 g/day) also modestly lower triglycerides (by 6-9%) in subjects with elevated triglycerides,21 although further study is needed.
What role do foods with plant sterols/stanols have in clinical practice?
The key recommendations of the EAS Consensus Panel are summarised in Table 1.
However, the cost of these products is also relevant when considering their use. Data from the UK (2005) indicate that the cost/kg of foods with added plant sterols can be 1.3- to 4-fold higher than that of their conventional counterparts,23 which can be a deterrent to their use. Indeed, data from the PrediMed study24 show that economic difficulties in Southern Europe appear to have a detrimental effect on adherence to a Mediterranean diet. Clearly, the cost issue warrants discussion between practising physicians and their patients.
It is clear that that we need a well-designed and adequately powered study of the effects of foods with added plant sterols/stanols on CVD outcomes. While the EAS Consensus Panel recognises that there are considerable practical issues, it is clear that only the conduct of such a study, with associated pharmacoeconomic analyses, will fully resolve outstanding questions regarding the role of these foods in CVD prevention. This Consensus view is also consistent with that of the Joint European Society of Cardiology/EAS guidelines for management of dyslipidemia.25
The reader is referred to the Full Position Statement (in press) which is available at http://www.sciencedirect.com/science/article/pii/S0021915013006941.
More evidence for eating nuts
There is accumulating evidence for the benefits of nut consumption as part of a healthy diet. Nuts contain a number of bioactive substances, including unsaturated fatty acids, fibre, vitamins, minerals, phenolic antioxidants and phytosterols.26 Thus, by virtue of their unique composition, nuts may beneficially impact health, potentially via effects on blood cholesterol, hyperglycaemia, insulin resistance, oxidative stress, inflammation or endothelial dysfunction.27-31 Regular nut consumption has also been associated with a reduced risk of type 2 diabetes mellitus or metabolic syndrome.32,33
A key question, therefore, is whether such effects may translate to reduction in mortality? Recently published findings from the Nurses’ Health Study and Health Professionals Follow-up Study now provide some insights into this challenging issue.1
This report evaluated data from these two studies including 76,464 women (Nurses’ Health Study) followed over the period 1980–2010, and 42,498 men (Health Professionals Follow-up Study), followed over the period 1986–2010. Subjects with a history of cancer, heart disease, or stroke were excluded from analyses. The studies evaluated nut consumption at baseline and every 2 to 4 years using validated food-frequency questionnaires. In 1980 and 1984 (Nurses’ Health Study) subjects were also asked how often each week they had consumed 1 oz of nuts (one serving), and this was later modified to include information on peanuts versus other nuts.
The primary endpoint of the study was death from any cause. There were 16,200 deaths over 30 years of follow-up of women in the Nurses’ Health Study and 11,229 deaths over 24 years of follow-up of men in the Health Professionals Follow-up Study. In both studies, there was a significant, dose-dependent inverse association between nut consumption and total mortality, after adjusting for potential confounders. Notably, daily consumption of nuts was associated with 20% reduction in all-cause death (pooled multivariate hazard ratio versus subjects who did not eat nuts 0.80, 95% CI, 0.73 to 0.86, p<0.0.001 for trend). Eating nuts at least 5 times per week also significantly reduced the risk of CV death by 25% (p<0.001) (Table 2).
While the authors acknowledge that the observational nature of these studies does not permit definitive conclusions regarding cause and effect, they highlight the strengths of the report. These include prospective design, large sample size, long duration of follow-up with low dropout rates and repeated assessment of diet and lifestyle. Additionally, while the food-frequency questionnaire was self-reported and therefore potentially subject to measurement error, nut consumption was relatively constant for individuals over the follow-up period.
Finally, the findings of this study are broadly consistent with those from the PrediMed study which showed that for high-risk primary prevention patients, a Mediterranean diet supplemented with ~1 oz nuts (15 g of walnuts, 7.5 g of hazelnuts and 7.5 g of almonds) significantly reduced the risk of CV events by 28% (p=0.03), almost entirely due to an effect of stroke.34
Taken together, these findings reinforce the critical role of dietary intervention, as part of a healthy lifestyle, as the fundamental first step in preventing CVD. The EAS Consensus Panel on Phytosterols Position Statement also suggests a potential role for functional foods across the spectrum of CV risk, although there is clearly a need for randomised controlled clinical trial data for definitive conclusions.