Cholesterol-lowering sterols and stanols

Reducing the rate of cardiovascular disease is a key public health challenge. Elevated LDL cholesterol is an important risk factor for myocardial infarction and stroke. There is evidence that a number of foods and food components can significantly reduce LDL cholesterol. Food components, such as plant sterols and stanols, soya protein, beta-glucans and tree nuts, may reduce LDL cholesterol. Various plant sterol and stanol-containing foods and supplements are commercially available.¹

Sterols and stanols

Sterols and stanols have a function in plants rather like that of cholesterol in humans. A high intake of these substances impairs uptake of cholesterol from the gut. They reduce total and LDL cholesterol and may beneficially influence other lipid variables such as apolipoprotein (apo) B/apo AI ratio and, in some studies, high-density lipoprotein (HDL) cholesterol and triglycerides (TGs).

Plant sterols/stanols may also affect inflammatory markers and coagulation parameters, as well as platelet and endothelial function.²

A daily consumption of 2 grams or greater of plant sterols/stanols can effectively lower total cholesterol and LDL cholesterol.³ It is difficult to consume this amount through typical foods (the usual dietary intake of plant sterols is around 250 to 500 milligrams per day), so stanol-enriched fortified foods have been developed and are widely available. The European Food Safety Authority permits manufacturers to use the following claim on fat spreads, salad dressings, mayonnaise and dairy products, such as milk and yoghurts:⁴

"Plant sterols have been shown to lower/reduce blood cholesterol. High cholesterol is a risk factor in the development of coronary heart disease."

LDL cholesterol is a causal factor for cardiovascular disease.⁵ However, LDL cholesterol is still a surrogate endpoint. To date, there have been no studies demonstrating a protective effect against cardiovascular disease from plant sterol use.⁶ By contrast, other interventions, such as the Mediterranean diet,⁷ smoking cessation,⁸ and lipid-lowering therapy with statins,⁹ do have direct evidence that demonstrates a preventative effect against cardiovascular disease.

This has led guideline committees to either eschew, or make limited recommendations for, the use of plant sterols/stenols. The National Institute for Health and Care Excellence (NICE) 2016 guidelines on cardiovascular risk reduction advise clinicians not to recommend plant stenols/sterols for cardiovascular disease prevention, based on the lack of direct evidence of clinical efficacy.¹⁰ The 2019 European Society for Cardiology and European Atherosclerosis Association (ESC/EAS) guidelines on the management of dyslipidaemias suggest plant sterols/stanols could be considered in some groups of patients (see below).⁶

Observational studies, using plasma plant sterol levels as a marker of exposure, have shown mixed results. Some reported higher levels of plant sterols in people with cardiovascular disease than people without, whereas others found the opposite, or no difference at all.¹¹ A 2012 meta-analysis of 17 studies found no evidence of an association between plasma plant sterol levels and cardiovascular disease risk.¹² However, methodologies varied between studies. It is also possible that plasma plant sterol levels are reflective of cholesterol absorption, and that therefore associations between plasma plant sterol levels and increased cardiovascular disease risk are confounded. More recently, a large observational study reported that the presence of a genetic variant that increases both cholesterol and plant sterol uptake was associated with an increased risk of cardiovascular disease; this risk was only partially explained by non-HDL cholesterol levels, leading the authors to speculate that the residual risk might be due to an atherogenic effect of plant sterols.¹³

Plant sterols and stanols

Sterols and stanols are ubiquitous in the plant world and are naturally found in fruits and vegetables. They are most effective when taken with food and are produced commercially to add to food.They are usually sold in the form of margarine but can occur in other forms like yoghurt. Rich natural sources include rice bran, avocado oil, original wheatgerm and extra virgin olive oil.

There do not seem to be any significant clinical differences between plant sterols and stanols in terms of their effects on total cholesterol, LDL cholesterol, HDL cholesterol, or TG levels.¹⁴

Stanols and sterols - effect on cholesterol

The evidence shows that there is considerable variation between individuals in response to stanols and sterols. They do tend to reduce LDL cholesterol and the effect is dose-related.. Daily consumption of 2 g of plant sterols or stanols has been shown to cause a 7-10% reduction in LDL cholesterol levels.³

There is evidence that plant-based diets, more broadly, are associated with cardiovascular health. The Mediterranean diet is considered a plant-based diet - it does not exclude meat, fish, and animal products completely, but favours plant-derived foods - and adherence to the Mediterranean diet seems to reduce cardiovascular risk.⁷ Vegetarian diets appear to lead to lower levels of total cholesterol and LDL cholesterol, although seemingly also lower levels of HDL cholesterol, which is thought to be protective.¹⁵

Conclusions about sterols, stanols and cholesterol

There is circumstantial evidence supporting the relationship between ingestion of sterols and stanols and a reduction in cardiovascular risk. It would seem to suggest the following conclusions:^{16 17}

• Observational and trial evidence to date suggests that stanols and sterols reduce LDL cholesterol in people with normal and moderately raised cholesterol and that this effect is related to dose.³ They are also effective in reducing LDL cholesterol in more severe cases, as in familial hypercholesterolaemia, including homozygous individuals.¹⁸

• Statins have a greater effect on serum lipids than diet, which has led to neglect of dietary manipulation, but sterols can be used in addition to statins to gain additional effect.¹⁹

• Plant sterol/stanol dietary supplements, as part of a healthy diet, may represent an effective means of delivering LDL cholesterol lowering similar to plant sterols/stanols delivered in various food formats.^{14 20}

• To date, there are no interventional studies that demonstrate an effect of plant sterol/stanol use on 'hard' endpoints, such as the development of cardiovascular disease, or death.⁶

Other benefits of sterols

There are some limited data from observational studies suggesting an association between dietary plant sterol/stanol intake and a reduced risk of certain cancers.²¹ There is currently insufficient evidence to demonstrate a protective effect against cancer from plant sterols and stanols in humans.

Safety and side-effects of sterols

Although sterols are natural products ubiquitous in food, their safety cannot be assumed.

• The ability to lower cholesterol is similar both in men and women; however, women seem to be much more susceptible to stanols causing impairment of the absorption of fat-soluble vitamins.

• Sterols are not recommended for pregnant or lactating women or for children aged under 5. This is because they have been shown to reduce the level of carotenoids, including vitamin A which is closely associated with fetal development.²² Moreover, the developing brain needs cholesterol. There are insufficient data to demonstrate safety of plant sterol supplementation in pregnancy and breastfeeding; therefore, they are generally advised to be avoided.

• Sitosterolemia is a rare autosomal recessive inherited disorder which is known to be associated with high maternal absorption of plant sterol and cholesterol. It results in coronary heart disease at an early age.²³ In addition, the presence of a genetic variant that leads to increased uptake of both cholesterol and plant sterols has been associated with an increased risk of cardiovascular disease, which is not fully explicable by serum non-HDL cholesterol levels.¹³ These findings have led to speculation that plant sterols might actually have a pro-atherogenic effect.¹¹

Recommendations for patients^{6 10}

NICE recommends that patients should not routinely be advised to take plant sterols and stanols for the primary or secondary prevention of cardiovascular disease. This is based on the absence of any interventional studies demonstrating an effect on cardiovascular morbidity or mortality.

The 2019 ESC/EAS guidelines took a different approach. Based on the findings that plant sterols and stanols can reduce LDL cholesterol by a modest amount, and the absence of evidence of harm from plant sterol consumption, these guidelines suggest that sterol/stanol- fortified foods can be considered for the following groups of people:

• People with high cholesterol levels and intermediate or low cardiovascular risk who do not qualify for lipid-lowering drug treatment.

• People with high or very high cardiovascular risk who do not achieve LDL cholesterol targets with statins, or cannot use statins.

• Adults and children (over the age of 6 years) with familial hypercholesterolaemia.

These recommendations are not without controversy; the German Cardiac Society criticised their inclusion, and called for evidence from randomised controlled trials with hard cardiovascular endpoints to be gathered before making recommendations for use.¹¹

It seems likely that, if plant stenols and sterols do have a protective effect on cardiovascular disease, this effect is modest. Pragmatically, it would make sense to focus on interventions where there is direct evidence of cardiovascular risk reduction, such as long-term dietary changes, regular physical activity, tobacco cessation, weight management, and, where appropriate, lipid-lowering drug therapy and blood pressure control. Some people might choose to take plant sterols and stanols as an adjunct to other risk-reduction measures, but should be aware that there is only indirect evidence of efficacy in preventing cardiovascular disease.