Arq Bras Cardiol abc Arquivos Brasileiros de Cardiologia Arq. Bras. Cardiol. 0066-782X 1678-4170 Sociedade Brasileira de Cardiologia - SBC Lzw5HRYHkYZQtBPwbp5mSwB S0066-782X2017001400475 10.5935/abc.20170158 Review Article Phytosterols in the Treatment of Hypercholesterolemia and Prevention of Cardiovascular Diseases Cabral Carlos Eduardo 1 Klein Márcia Regina Simas Torres 1 2 Universidade do Estado do Rio de Janeiro Hospital Universitário Pedro Ernesto Divisão de Nutrição Rio de Janeiro RJ Brazil Divisão de Nutrição - Hospital Universitário Pedro Ernesto - Universidade do Estado do Rio de Janeiro (UERJ), Rio de Janeiro, RJ - Brazil Universidade do Estado do Rio de Janeiro Universidade do Estado do Rio de Janeiro Instituto de Nutrição Departamento de Nutrição Aplicada Rio de Janeiro RJ Brazil Departamento de Nutrição Aplicada - Instituto de Nutrição - Universidade do Estado do Rio de Janeiro, Rio de Janeiro, RJ - Brazil Universidade do Estado do Rio de Janeiro Mailing Address: Márcia Regina Simas Torres Klein Avenida 28 de Setembro, 87 - rooms 363 and 367. Postal Code 20551-030, Vila Isabel, RJ - Brazil. E-mail: marciarsimas@gmail.com

Author contributions

Writing of the manuscript: Cabral CE, Klein MRST; Critical revision of the manuscript for intellectual content: Klein MRST.

Potential Conflict of Interest

No potential conflict of interest relevant to this article was reported.

 11 2017 109 5 475 482 06 04 2017 22 06 2017 05 07 2017 This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract

Phytosterols are bioactive compounds found in foods of plant origin, which can be divided into plant sterols and plant stanols. Clinical studies consistently indicate that the intake of phytosterols (2 g/day) is associated with a significant reduction (8-10%) in levels of low-density lipoprotein cholesterol (LDL-cholesterol). Thus, several guidelines recommend the intake of 2 g/day of plant sterols and/or stanols in order to reduce LDL-cholesterol levels. As the typical western diet contains only about 300 mg/day of phytosterols, foods enriched with phytosterols are usually used to achieve the recommended intake. Although phytosterols decrease LDL-cholesterol levels, there is no evidence that they reduce the risk of cardiovascular diseases; on the contrary, some studies suggest an increased risk of atherosclerosis with increasing serum levels of phytosterols. This review aims to address the evidence available in the literature on the relationship between phytosterols and risk of cardiovascular disease.

 Keywords Cardiovascular Diseases Phytosterols Atherosclerosis Cholesterol, LDL Introduction

Cardiovascular diseases (CVD) remain the main cause of mortality worldwide, accounting for about 30% of all deaths.1 During the last two decades, deaths due to CVD decreased in developed countries but increased sharply in low- and middle-income countries.1,2

Atherosclerosis is the main pathological process that leads to the development of CVD, including acute myocardial infarction (AMI), heart failure, and stroke.3 Early identification of risk factors for CVD is fundamental for the prevention of the onset and/or progression of atherosclerosis. The main risk factors for atherosclerosis include smoking, hypertension, diabetes mellitus, advanced age, family history of CVD, and dyslipidemia.4,5

The fundamental role of dyslipidemia - especially hypercholesterolemia - in the development of CVD has already been confirmed.4 Through a wide range of plasma cholesterol concentrations, there is a strong positive linear correlation between risk of CVD and levels of total cholesterol and low-density lipoprotein cholesterol (LDL-cholesterol) levels. Additionally, it has been demonstrated that a reduction in LDL-cholesterol levels reduces the risk of CVD.4,6,7

There is evidence that elevated serum LDL-cholesterol levels may cause atherosclerotic CVD independently of other risk factors.8 Dyslipidemia can be considered a primary risk factor for atherosclerotic CVD and may be a prerequisite for atherosclerosis, occurring before the participation of other risk factors.5 The increase in serum LDL-cholesterol concentrations appears to be necessary for atherogenesis. LDL comprises more than 75% of the atherogenic lipoproteins, with the remaining including cholesterol-rich remnants of lipoproteins rich in triglycerides (chylomicrons and very-low-density lipoproteins; VLDL). When LDL infiltrates into the arterial wall, it initiates and promotes atherosclerosis.8

According to the World Health Organization (WHO), 39% of adults (> 25 years) worldwide have increased total cholesterol concentrations (> 190 mg/dL). The prevalence is greater in Europe (54%), followed by the Americas (48%).9

The treatment of hypercholesterolemia must include nonpharmacological measures, which are recommended for all patients, as well as the use of pharmacological therapy that may be indicated in specific situations.10 The drugs currently available for the treatment of hypercholesterolemia include statins (hydroxy-methylglutaryl-coenzyme A [HMG-CoA] reductase inhibitors), ezetimibe (a selective inhibitor of cholesterol absorption), and resins or bile acid sequesters. Statins should be used as the first choice due to their powerful effect on LDL-cholesterol reduction (25-55%) and because they are the most study-validated drugs for reduction of cardiovascular events. Ezetimibe has a moderate effect on LDL-cholesterol reduction (15-25%). Resins may be associated with statins when the target LDL-cholesterol is not achieved despite the use of statins, leading to a reduction of 30% in LDL-cholesterol levels.4,8,10

Nonpharmacological treatment of dyslipidemia must include changes in dietary habits and physical activity, in addition to weight loss, when indicated.10 In the nutritional approach, intake of saturated fatty acids and trans fatty acids must be limited as well as the intake of cholesterol, in addition to increasing the intake of soluble fiber. The consumption of phytosterols is also indicated for the treatment of hypercholesterolemia, according to several guidelines and consensuses of different societies worldwide.4,5,8,10-12 There is consistent evidence that the intake of phytosterols (2 g/day) is associated with a significant reduction in LDL-cholesterol (8 - 10%).11 However, there are no data indicating that the consumption of phytosterols may reduce the risk of CVD. On the contrary, some studies suggest that the concomitant elevation in plasma concentration of phytosterols can increase the risk of development of atherosclerosis.13,14

This review aims at addressing the evidence available in the literature on the relationship between phytosterols and risk of CVD.

Phytosterols Definition, classification, and food sources

The term "phytosterols" is used to describe plant sterols and their saturated derivatives, plant stanols.15,16 Phytosterols are bioactive compounds found naturally in foods of plant origin and present a chemical structure similar to that of cholesterol,17 which is found only in foods of animal origin. More than 250 phytosterols have already been identified.15 The plant sterols more commonly found in the diet are beta-sitosterol, campesterol, and stigmasterol. In regards to plant stanols, beta-sitostanol, and campestanol are the two most common types.18

Food sources of phytosterols include vegetable oils, mainly corn (909 mg/100 mL), sunflower (411 mg/100 mL), soybean (320 mg/100 mL), and olive (300 mg/100 mL); oleaginous fruits such as almonds (183 mg/100 g); cereals like wheat germ (344 mg/100 g), and wheat bran (200 mg/100 g); in addition to fruits and vegetables, such as passion fruit (44 mg/100 g), orange (24 mg/100 g), and cauliflower (40 mg/100 g).18 A typical western diet contains approximately 300 mg of sterols and 30 mg of plant stanols,17 while vegetarian diets can achieve a higher content (300 - 500 mg/day).18 This amount of phytosterols present in a regular diet is considered small to achieve the recommended daily intake of phytosterols able to present therapeutic effects on LDL-cholesterol reduction (~2 g/day), and it is generally required the consumption of foods enriched with phytosterols or, alternatively, the use of supplements of phytosterols.16,18 In Brazil, some processed foods enriched with phytosterols are available, including margarine, yogurt, and milk.

 Mechanism of action on cholesterol

The main mechanism by which phytosterols lower LDL-cholesterol levels is through a reduction (30 - 50%) in the intestinal absorption of cholesterol.15,16 This reduction may be mediated by some mechanisms, in particular, the competition with cholesterol by the solubilization in mixed micelles in the intestinal lumen, reducing the amount of cholesterol available for absorption.15,19 Other proposed mechanisms include: (1) modification in the expression of genes that encode the proteins that carry sterols, such as the Niemann-Pick C1-like 1 (NPC1-L1) protein, reducing the transport of cholesterol to the enterocyte, or ATP-binding cassette transporters (ABCG5 and ABCG8), promoting the efflux of cholesterol from the enterocytes to the intestinal lumen; (2) reduced rate of cholesterol esterification in the enterocyte; and (3) increased removal of cholesterol from the body through the transintestinal cholesterol excretion (TICE).17 In response to a decrease in the absorption of dietary cholesterol, hepatic synthesis of cholesterol seems to increase, but the increase in hepatic release of cholesterol is not sufficient to compensate for the lower absorption of dietary cholesterol.16

Intestinal absorption of plant sterols (< 2%) and stanols (< 0.2%) is much lower than that of cholesterol (~50%).17 As a result of the low absorption and efficient biliary excretion after hepatic uptake, circulating levels of phytosterols are very low, ranging from 0.3 to 1.0 mg/dL for plant sterols and 0.002 to 0.012 mg/dL for plant stanols. The distribution of phytosterols through the main classes of lipoproteins is similar to that of cholesterol; therefore, they circulate mainly in LDL particles (65 - 70%).11

Cholesterol-lowering effect of phytosterols

Since the late 1950s, numerous studies have consistently indicated that foods enriched with phytosterols reduce the concentrations of LDL-cholesterol.20-24 Table 1 shows some randomized, placebo-controlled clinical trials published since 2010 that evaluated the effects of foods enriched with phytosterols on the cholesterolemia. The Table demonstrates that the dose is around 2 - 4 g/day and the reduction in LDL-cholesterol is ~10%. For example, the study by Párraga-Martínez et al.25 evaluated the intake of 2 g/day of plant stanols during 12 months and observed an 11% reduction in LDL-cholesterol levels. The study of Vásquez-Trespalacios & Romero-Palacio (2014)26 evaluated the intake of 4 g/day of plant stanols and observed after 4 weeks a 10.3% decrease in LDL-cholesterol levels. Among the studies listed in Table 1, the study that used the highest dose of phytosterols (8.8 g/day of plant stanols) was the one conducted by Gylling et al. (2010),27 which showed a 17.1% reduction in LDL-cholesterol levels.

Randomized clinical trials evaluating the effects of supplementation of phytosterols on cholesterolemia
Authors (year) n Type of phytosterol (food/supplement) Dose of phytosterol (g/day) Duration ↓ LDL-cholesterol (%) P value (versus control group)
Studies with foods enriched with phytosterols
Gylling et al. (2010)27 49 individuals with mild-to-moderate hypercholesterolemia Stanols (spread and drink) 8.8 10 weeks 17.1 0.01
Gylling et al. (2013)39 92 asymptomatic individuals (not using lipid-lowering drugs) Stanols (spread) 3 6 months 10.2 0.001
Buyuktuncer et al. (2013)40 70 individuals with mild-to-moderate hypercholesterolemia Stanols (yogurt) 1.9 4 weeks 6.3 0.005
Vásquez-Trespalacios & Romero-Palacio (2014)26 40 individuals with moderate hypercholesterolemia Stanols (yogurt) 4 4 weeks 10.3 < 0.01
Ras et al. (2015)41 240 individuals with hypercholesterolemia Sterols (spread) 3 12 weeks 6.7 < 0.05
Párraga-Martinez et al. (2015)25 182 adults with hypercholesterolemia Stanols (yogurt) 2 12 months 11 0.01
Studies with capsules or tablets
Maki et al. (2012)32 32 subjects with primary hypercholesterolemia Sterols/Stanols (pill) 1.8 6 weeks 4.9 < 0.05
Maki et al. (2013)29 28 subjects with primary hypercholesterolemia Sterols/Stanols (softgel capsule) 1.8 6 weeks 9.2 < 0.001
Ottestad et al. (2013)30 41 individuals with total cholesterol 180 - 300 mg/dL Sterols/Stanols (softgel capsule) 2 4 weeks 2.7 0.32
McKenney et al. (2014)31 30 adults with familial hypercholesterolemia Sterols/Stanols (softgel capsule) 1.8 6 weeks 4.3 < 0.01

LDL-cholesterol: low-density lipoprotein cholesterol.

Recent meta-analyses confirmed the cholesterol-lowering effect of phytosterols, in addition to comparing the effects of sterols with those of stanols, and evaluating the dose-response relationship.21-24 The dose-response relationship presented a slight variation among the meta-analyses, and there is still no consensus. A meta-analysis conducted by Ras et al.24 included 124 studies with a mean phytosterol dose of 2.1 g/day (range 0.2 to 9.0 g/day). The intake of 0.6 - 3.3 g/day was associated with a gradual decrease in the concentration of LDL-cholesterol of 6 - 12%. Plant sterols and stanols had comparable effects. The studies with doses exceeding 4 g/day were not grouped together, because they were few and had large dose variations. The authors concluded that the LDL-cholesterol reducing effect of both plant sterols and stanols increased until an intake of approximately 3 g/day, with a mean effect of 12%.24 A meta-analysis conducted by Talati et al.22 compared the effects of plant sterols and stanols on LDL-cholesterol and also observed no significant differences.

The data indicating the cholesterol-lowering effect of foods enriched with phytosterols derive from intervention studies with good methodological quality, conducted with a relatively large number of participants, and the results are generally consistent.28 According to several international scientific societies, the regular use of 2 g/day of phytosterols under supervision can be recommended for a 10% LDL-cholesterol reduction.4,5,8,10-12

Leaving the scenario of fortified foods, some recent studies have evaluated the effects of phytosterols in tablets or capsules,29-32 with the objective of evaluating whether this form of supplementation (considered more practical by many authors) would also be effective in lowering cholesterol. The study by Maki et al.29 used softgel capsules, providing 1.8 g/day of esterified sterols/stanols in conjunction with lifestyle changes recommended by the National Cholesterol Education Program (NCEP) for 6 weeks and observed a 9.2% reduction in LDL-cholesterol levels. A significant reduction in LDL-cholesterol levels was also observed in studies conducted by Maki et al.32 and McKenney et al..31 However, the study conducted by Ottestad et al.30 did not observe a significant reduction in LDL-cholesterol levels. A recent meta-analysis33 including eight studies published from 1992 to 2013 with a duration of 4 - 6 weeks and doses of phytosterols between 1 to 3 g/day in tablets or capsules observed a significant reduction in LDL-cholesterol (on average 12 mg/dL), which was similar to that observed with food enriched with phytosterols. Therefore, despite the lack of consensus, most studies indicate that the use of phytosterols in tablets or capsules can be effective in reducing LDL-cholesterol levels.

There is evidence that the consumption of phytosterols in association with lipid-lowering therapy is able to promote a further reduction in serum cholesterol levels. These benefits have been observed in association with statins34-36 and also with ezetimibe.37,38 The meta-analysis developed by Han et al.36 included 15 randomized clinical trials that evaluated the effect of diets enriched with phytosterols in patients using statins. The phytosterols in combination with statins, compared with statins alone, produced a significant reduction of 12 mg/dL in LDL-cholesterol levels.

 Phytosterols and cardiovascular disease

The direct relationship between intake of foods enriched with phytosterols and CVD risk has not been investigated in randomized clinical trials. It has been estimated that it would be necessary to follow up at least 33,000 individuals for about 10 years for a proper assessment of the effects of phytosterols on hard endpoints, hindering the viability of such studies.42

By inference based on the cardioprotective efficacy of other cholesterol-lowering interventions, some authors consider that phytosterols may reduce cardiovascular risk; however, this statement should not be performed until studies proving this fact are available.43

- Serum levels of phytosterols

The speculation in regards to a potential deleterious effect of phytosterols has been largely motivated by the fact that phytosterolemia (also known as sitosterolemia), a rare autosomal recessive disease, is characterized by a 50-fold increased circulating concentration of plant sterols and may be associated with early atherosclerosis. However, the consumption of foods enriched with phytosterols is associated with a much lower increase (around twice) in circulating plant sterols.44

Several studies have evaluated the association between plasma phytosterol concentration and CVD; however, the results are conflicting. Some studies have found a positive association between serum levels of phytosterols (or the relationship phytosterols/cholesterol) and risk of CVD;13,14 while others did not observe any association or even found an inverse association.45-47 Genser et al.48 published a systematic review and meta-analysis based on 17 studies involving 11,182 individuals and found no evidence of an association between serum concentration of phytosterols and development of CVD. The authors of this meta-analysis attributed the great divergence in the results of the studies to the different designs of studies and adjustments for potential confounding variables. They suggest that biases can occur if the investigators fail to make appropriate adjustments, mainly for serum levels of lipoproteins, in particular for LDL-cholesterol.48 Another possibility is the fact that circulating phytosterols alone do not increase the risk of CVD but are rather only markers of cholesterol absorption.49

- Intermediate markers of cardiovascular risk

Due to the absence of studies evaluating cardiovascular outcomes, the investigation of intermediate risk markers for CVD represents an acceptable and viable form to evaluate the relationship between phytosterols and cardiovascular risk. Currently, there are available studies assessing endothelial dysfunction, arterial stiffness, diameter of the retinal vessels, and inflammation of low degree.39,41,50-54

In a study conducted by Gylling et al.,39 the consumption of plant stanols (3 g/day) for 6 months showed beneficial effects on arterial stiffness, especially in men. In addition, endothelial function, assessed by peripheral arterial tonometry, improved with a reduction in LDL-cholesterol and non-high-density lipoprotein (non-HDL) cholesterol. A study conducted by Heggen et al.52 tested the effects of two margarines enriched with plant sterols (2 g/day) from two different vegetable oils during 4 weeks. The authors observed a significant reduction in E-selectin and plasminogen activator inhibitor 1 (PAI-1) with the ingestion of only one of the margarines. In this study, there was no significant reduction in vascular cellular adhesion molecule-1 (VCAM-1) and tumor necrosis factor alpha (TNF-α) with any of the margarines, and also no association was observed between LDL-cholesterol reduction and changes in E-selectin and total PAI-1.52

On the other hand, supplementation with 3 g/day of plant sterols for 12 weeks in 240 subjects with hypercholesterolemia did not result in beneficial effects on arterial stiffness and endothelial function.41,54 In this study, the endothelial function was assessed by flow-mediated dilation41 and circulating biomarkers: intercellular adhesion molecule-1 (ICAM-1), VCAM-1, and E-selectin.54

In two crossover clinical trials including children with familial hypercholesterolemia, the consumption of phytosterols during 4 weeks failed to improve endothelial function assessed by flow-mediated dilation, although it induced a significant reduction in LDL-cholesterol levels.50,51

A randomized clinical trial conducted by Kelly et al.53 evaluated the effects of consumption over the long term (85 weeks) of plant sterols and stanols on the diameter of retinal vessels (microcirculation). The study included three groups of patients who consumed margarine enriched with plant sterols (2.5 g/day), margarine enriched with plant stanols (2.5 g/day), and margarine without phytosterols. There were no significant changes in venular diameter in the three groups, but the changes in serum concentrations of campesterol (a type of plant sterol) were positively associated with the changes in venular diameter, regardless of LDL-cholesterol level (r = 0.39, p = 0.03).

In regards to inflammation, there was no significant reduction in any of the markers evaluated in the study conducted by Ras et al.54: C-reactive protein (CRP), serum amyloid A, interleukin (IL)-6, IL-8, TNF-α, and ICAM-1. In a systematic review and meta-analysis recently published, Rocha et al.55 evaluated the effect of consumption of phytosterols on inflammatory markers, particular on CRP. The study included 20 randomized clinical trials (n = 1,308) involving foods enriched with phytosterols as active treatment. The reduction in CRP concentration with the consumption of phytosterols was 0.10 mg/dL, which did not reach statistical significance.55

The results of these studies evaluating the effects of phytosterols on intermediaries markers of cardiovascular risk observed no consistent beneficial effects. Thus, there is no current evidence that the use of phytosterols may reduce the risk of CVD by acting on these markers.

 - Intake of oxidized phytosterols

Recent publications have alerted to another potential deleterious effect of phytosterols: the intake of oxidized phytosterols. Plant sterols (but not stanols, because they are saturated) may oxidate, forming oxidized phytosterols and, similarly to what is observed with cholesterol oxidation, these substances are believed to be atherogenic.56 However, in studies with humans, there is still no consensus on whether the intake of foods enriched with sterols is able to increase the serum concentration of oxidized phytosterols. For example, in the clinical randomized, crossover trial conducted by Baumgartner et al. (2013),57 43 healthy individuals consumed during 4 weeks margarine enriched with sterols (3 g/day), margarine enriched with stanols (3 g/day), and a control margarine. The consumption of margarine enriched with sterols did not increase the serum concentration of oxidized phytosterols.57 Another study by the same group58 investigated the effects of intake of sterols on the concentration of oxidized phytosterols during the postprandial period. In this study, the individuals consumed a drink containing none or 3 g of plant sterols or stanols. Blood samples were collected for up to 8 h, and 4 hours later, the individuals received a second drink (without sterols or stanols). The concentration of oxidized phytosterols increased significantly after consumption of the meal with sterols in comparison with the meal with stanols and the control meal. This increase was only observed after the consumption of the second drink and the authors concluded that it is still unclear whether the increase in oxidized phytosterols in the postprandial period is due to absorption or endogenous formation. Therefore, until the present moment, there is no consensus on the role of oxidized phytosterols in the development of CVD.

 Phytosterols and liposoluble vitamins

Considering that phytosterols reduce the intestinal absorption of cholesterol, it is reasonable to imagine that these substances may also reduce the absorption of liposoluble vitamins and antioxidants. The serum levels of vitamins A, D, and K1 are generally not affected by the consumption of phytosterols.59 However, some studies suggest that phytosterols may promote a modest reduction in plasma concentration of carotenoids (mainly β-carotene, α-carotene, and lycopene)27,60 and tocopherols,61 but other studies have not observed this fact.62,63 A recently published meta-analysis evaluated the effects of phytosterol consumption in plasma concentrations of liposoluble vitamins and carotenoids. It included 41 randomized clinical trials (n = 3,306) with a mean phytosterol intake of 2.5 g/day. In the analyses adjusted for total cholesterol, there was a significant reduction in the concentration of hydrocarbon carotenoids (β-carotene, α-carotene, and lycopene) and some oxygenated carotenoids (zeaxanthin and cryptoxanthin). In contrast, there was no significant reduction in the concentration of tocopherol, vitamin D, or retinol. A very important finding of this meta-analysis was that the concentration of these substances remained within the normal range, giving no indication that the observed reductions could have negative health implications.64 Noakes et al.65have demonstrated that it is possible to avoid reductions in plasma carotenoid concentrations during the consumption of phytosterols through an increase in daily consumption of carotenoid-rich fruits and vegetables.

 Is the consumption of phytosterols safe?

There are still no available studies with long-term follow-up ensuring the safety of regular consumption of products enriched with phytosterols, as highlighted in recent publications of the European Society of Cardiology / European Atherosclerosis Society12 and the American Heart Association / American College of Cardiology.66 However, based on the absence of adverse effects in short-term studies and experimental studies, several authors consider that the consumption of phytosterols is safe and may be indicated for lowering cholesterol, including in association with drug therapy.11,59,63,67,68 Furthermore, different scientific societies recommended the use of phytosterols in the treatment of hypercholesterolemia.4,5,8,10-12,28 It is important to note that phytosterol supplementation is contraindicated in the rare patients presenting phytosterolemia (or sitosterolemia).16,67

The addition of phytosterols to industrialized food as an ingredient to reduce cholesterol has already been approved by several regulatory agencies around the world, including Health Canada, U.S. Food and Drug Administration (FDA), European Food and Safety Authority (EFSA), Food Standards Australia New Zealand (FSANZ),16 and National Health Surveillance Agency (ANVISA) in Brazil.69

According to ANVISA, foods enriched with phytosterols should display the following label information: "Phytosterols help reduce the absorption of cholesterol. Their consumption must be associated with a balanced diet and a healthy lifestyle." ANVISA determines that to display this information, the portion of the product ready for consumption should provide at least 0.8 g of free phytosterols. In addition, the label of these products should include phrases such as: "The product is not suitable for children younger than 5 years, and pregnant or nursing women."69

Final considerations

The European Atherosclerosis Society recently published a consensus on phytosterols that concluded that based on the reducing effect of LDL-cholesterol and absence of adverse signs, the consumption of foods enriched with phytosterols may be considered: (1) in individuals with hypercholesterolemia presenting intermediate or low cardiovascular risk without indication of pharmacotherapy, (2) as an adjunct to pharmacological therapy in patients with high and very high cardiovascular risk who fail to achieve the goals of LDL-cholesterol with statins or are intolerant to statins, and (3) in adults and children (> 6 years) with familial hypercholesterolemia, along with lifestyle changes and drug therapy.11

Most guidelines and consensus on the treatment of dyslipidemia and/or prevention of CVD recommend the intake of phytosterols in the amount of approximately 2 g/day with the goal of reducing LDL-cholesterol by approximately 10%, in association with lifestyle changes.4,5,8,10-12,28

Currently, the knowledge about the relationship between consumption of phytosterols and risk of CVD is incomplete. The available evidence does not confirm that phytosterols may confer cardiovascular protection and also does not show deleterious effects. Further studies are needed, especially with long-term supplementation of phytosterols.

Sources of Funding

There were no external funding sources for this study.

Study Association

This article is part of the Clinical Nutrition Residency Conclusion Paper submitted by Carlos Eduardo Cabral, from Universidade do Estado do Rio de Janeiro.

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Baumgartner S Mensink RP Konings M Schott HF Friedrichs S Husche C Postprandial plasma oxyphytosterol concentrations after consumption of plant sterol or stanol enriched mixed meals in healthy subjects Steroids 2015 99 B 281 286 10.1016/j.steroids.2015.01.017 59 Rondanelli M, Monteferrario F, Faliva MA, Perna S, Antoniello N. Key points for maximum effectiveness and safety for cholesterol-lowering properties of plant sterols and use in the treatment of metabolic syndrome. J Sci Food Agric. 2013;93(11):2605-10. Doi: 10.1002/jsfa.6174 Rondanelli M Monteferrario F Faliva MA Perna S Antoniello N Key points for maximum effectiveness and safety for cholesterol-lowering properties of plant sterols and use in the treatment of metabolic syndrome J Sci Food Agric 2013 93 11 2605 2610 10.1002/jsfa.6174 60 Tuomilehto J, Tikkanen MJ, Högström P, Keinänen-Kiukaanniemi S, Piironen V, Toivo J, et al. Safety assessment of common foods enriched with natural nonesterified plant sterols. Eur J Clin Nutr. 2009;63(5):684-91. doi: 10.1038/ejcn.2008.11. Tuomilehto J Tikkanen MJ Högström P Keinänen-Kiukaanniemi S Piironen V Toivo J Safety assessment of common foods enriched with natural nonesterified plant sterols Eur J Clin Nutr 2009 63 5 684 691 10.1038/ejcn.2008.11 61 Richelle M, Enslen M, Hager C, Groux M, Tavazzi I, Godin JP, et al. Both free and esterified plant sterols reduce cholesterol absorption and the bioavaibility of beta-carotene and alpha-tocopherol in normocholesterolemic humans. Am J Clin Nutr. 2004;80(1):171-7. PMID: 15213045. Richelle M Enslen M Hager C Groux M Tavazzi I Godin JP Both free and esterified plant sterols reduce cholesterol absorption and the bioavaibility of beta-carotene and alpha-tocopherol in normocholesterolemic humans Am J Clin Nutr 2004 80 1 171 177 15213045 62 Mensink RP, de Jong A, Lütjohann D, Haenen GR, Plat J. Plant stanols dose-dependently decrease LDL-cholesterol concentrations, but not cholesterol-standardized fat-soluble antioxidant concentrations, at intakes up to 9 g/d. Am J Clin Nutr. 2010;92(1):24-33. doi: 10.3945/ajcn.2009.29143. Mensink RP de Jong A Lütjohann D Haenen GR Plat J Plant stanols dose-dependently decrease LDL-cholesterol concentrations, but not cholesterol-standardized fat-soluble antioxidant concentrations, at intakes up to 9 g/d Am J Clin Nutr 2010 92 1 24 33 10.3945/ajcn.2009.29143 63 Rudkowska I, AbuMweis SS, Nicolle C, Jones PJ. Cholesterol-lowering efficacy of plant sterols in low-fat yogurt consumed as a snack or with a meal. J Am Coll Nutr. 2008;27(5):588-95. PMID: 18845709. Rudkowska I AbuMweis SS Nicolle C Jones PJ Cholesterol-lowering efficacy of plant sterols in low-fat yogurt consumed as a snack or with a meal J Am Coll Nutr 2008 27 5 588 595 18845709 64 Baumgartner S, Ras RT, Trautwein EA, Mensink RP, Plat J. Plasma fat-soluble vitamin and carotenoid concentrations after plant sterol and plant stanol consumption: a meta-analysis of randomized controlled trials. Eur J Nutr. 2017;56(3):909-23. doi 10.1007/s00394-016-1289-7. Baumgartner S Ras RT Trautwein EA Mensink RP Plat J Plasma fat-soluble vitamin and carotenoid concentrations after plant sterol and plant stanol consumption: a meta-analysis of randomized controlled trials Eur J Nutr 2017 56 3 909 923 10.1007/s00394-016-1289-7 65 Noakes M, Clifton P, Ntanios F, Shrapnel W, Record I, McInerney J. An increase in dietary carotenoids when consuming plant sterols or stanols is effective in maintaining plasma carotenoid concentrations. Am J Clin Nutr. 2002;75(1):79-86. PMID: 11756063. Noakes M Clifton P Ntanios F Shrapnel W Record I McInerney J An increase in dietary carotenoids when consuming plant sterols or stanols is effective in maintaining plasma carotenoid concentrations Am J Clin Nutr 2002 75 1 79 86 11756063 66 Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Bum CB, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129(25 Suppl 2):S1-S45. doi: 10.1161/01.cir.0000437738.63853.7a. Stone NJ Robinson JG Lichtenstein AH Bairey Merz CN Bum CB 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines Circulation 2014 129 25 2 S1 S45 10.1161/01.cir.0000437738.63853.7a 67 Hunter PM, Hegele RA. Functional foods and dietary supplements for the management of dyslipidaemia. Nat Rev Endocrinol. 2017;13(5):278-88. doi: 10.1038/nrendo.2016.21. Hunter PM Hegele RA Functional foods and dietary supplements for the management of dyslipidaemia Nat Rev Endocrinol 2017 13 5 278 288 10.1038/nrendo.2016.21 68 Cofán M, Ros E. Clinical application of plant sterols and stanols products. J AOAC Int. 2015;98(3):701-6. doi: 10.5740/jaoacint.SGECofan. Cofán M Ros E Clinical application of plant sterols and stanols products J AOAC Int 2015 98 3 701 706 10.5740/jaoacint.SGECofan 69 Brasil. Ministério da Saúde. Agência Nacional de Vigilância Sanitária. ANVISA Alimentos com alegações de propriedades funcionais e ou de saúde. [Acesso em 2017 feb 16]. Disponível em http://portal.anvisa.gov.br/alimentos/alegacoes. Brasil Ministério da Saúde Agência Nacional de Vigilância Sanitária ANVISA Alimentos com alegações de propriedades funcionais e ou de saúde 2017 feb 16 Disponível em http://portal.anvisa.gov.br/alimentos/alegacoes Artigo de Revisão Fitosteróis no Tratamento da Hipercolesterolemia e Prevenção de Doenças Cardiovasculares Cabral Carlos Eduardo 1 Klein Márcia Regina Simas Torres 1 2 Divisão de Nutrição - Hospital Universitário Pedro Ernesto - Universidade do Estado do Rio de Janeiro (UERJ), Rio de Janeiro, RJ - Brasil Departamento de Nutrição Aplicada - Instituto de Nutrição - Universidade do Estado do Rio de Janeiro, Rio de Janeiro, RJ - Brasil Correspondência: Márcia Regina Simas Torres Klein Avenida 28 de Setembro, 87 - salas 363 e 367. CEP 20551-030, Vila Isabel, RJ - Brasil. E-mail: marciarsimas@gmail.com

Contribuição dos autores

Redação do manuscrito: Cabral CE, Klein MRST; Revisão crítica do manuscrito quanto ao conteúdo intelectual importante: Klein MRST.

Potencial conflito de interesses

Declaro não haver conflito de interesses pertinentes.

 Resumo

Os fitosteróis são compostos bioativos encontrados em alimentos de origem vegetal e que podem ser divididos em esteróis vegetais e estanóis vegetais. Estudos clínicos indicam de forma consistente que a ingestão de fitosteróis (2 g/dia) está associada a uma redução significativa (8-10%) de níveis de colesterol da lipoproteína de baixa densidade (LDL-C). Desta forma, diversas diretrizes recomendam a ingestão de 2 g/dia de esteróis e/ou estanóis vegetais com o objetivo de reduzir os níveis de LDL-C. Como uma dieta ocidental típica contém apenas cerca de 300 mg/dia de fitosteróis, normalmente são utilizados alimentos enriquecidos com fitosteróis para alcançar a ingestão recomendada. Apesar dos fitosteróis reduzirem os níveis de LDL-C, não há evidências de que reduzam o risco de doenças cardiovasculares. Pelo contrário, alguns estudos sugerem que a elevação na concentração sérica de fitosteróis possa estar associada com aumento no risco de aterosclerose. Esta revisão tem como objetivo abordar as evidências disponíveis na literatura sobre a relação entre fitosteróis e risco de doenças cardiovasculares.

 Palavras-chave Doenças Cardiovasculares Fitosteróis Colesterol Aterosclerose LDL-Colesterol Introdução

As doenças cardiovasculares (DCV) permanecem como a principal causa de mortalidade em todo o mundo, sendo responsáveis por cerca de 30% de todas as mortes.1 Durante as últimas duas décadas, as mortes por DCV apresentaram uma redução nos países desenvolvidos, mas aumentaram de forma acentuada nos países de baixa e média renda.1,2

A aterosclerose é o principal processo patológico que leva ao desenvolvimento das DCV, incluindo o infarto agudo do miocárdio (IAM), a insuficiência cardíaca e o acidente vascular encefálico (AVE).3 A identificação precoce dos fatores de risco para DCV é fundamental para a prevenção do aparecimento e/ou progressão da aterosclerose. Dentre os principais fatores de risco para a aterosclerose, destacam-se o tabagismo, a hipertensão arterial, o diabetes mellitus, a idade avançada, a história familiar de DCV e a dislipidemia.4,5

No desenvolvimento das DCV, já está comprovado o papel fundamental da dislipidemia, especialmente da hipercolesterolemia.4 Através de uma ampla faixa de concentração plasmática de colesterol, existe uma forte correlação linear positiva entre risco de DCV e níveis de colesterol total, assim como níveis de colesterol da lipoproteína de baixa densidade (LDL-C). Além disto, já foi demonstrado que a redução dos níveis de LDL-C reduz o risco de DCV.4,6,7

Existem evidências de que níveis séricos elevados de LDL-C podem causar DCV aterosclerótica independentemente de outros fatores de risco.8 A dislipidemia pode ser considerada um fator de risco primário para a DCV aterosclerótica, podendo ser um pré-requisito para a aterosclerose, ocorrendo antes da participação de outros fatores de risco.5 O aumento na concentração sérica de LDL-C parece ser necessário para a aterogênese. A LDL representa mais de 75% das lipoproteínas aterogênicas; as demais são os remanescentes enriquecidos em colesterol das lipoproteínas ricas em triglicerídeos (quilomícrons e lipoproteína de muito baixa densidade; VLDL). Ao penetrar na parede arterial, a LDL inicia e promove a aterosclerose.8

De acordo com a Organização Mundial de Saúde (OMS), 39% dos adultos (> 25 anos) em todo o mundo têm concentrações elevadas de colesterol total (> 190 mg/dL). A prevalência é mais alta na Europa (54%), seguida das Américas (48%).9

O tratamento da hipercolesterolemia deve incluir medidas não farmacológicas, que estão recomendadas para todos os pacientes, assim como o uso da terapia farmacológica que pode ser indicada em situações específicas.10 As drogas disponíveis atualmente para o tratamento da hipercolesterolemia incluem as estatinas (inibidores da hidroximetilglutaril coenzima A [HMG-CoA] redutase), a ezetimiba (inibidor seletivo da absorção do colesterol) e as resinas ou sequestradores dos ácidos biliares. As estatinas devem ser utilizadas como primeira escolha, por apresentarem potente efeito na redução do LDL-C (25-55%) e por serem as drogas mais validadas por estudos na redução de eventos cardiovasculares. A ezetimiba apresenta um efeito moderado na redução do LDL-C (15-25%). As resinas podem ser associadas às estatinas quando a meta de LDL-C não é alcançada apesar do uso de estatinas, levando a uma redução de 5 a 30% nos níveis de LDL-C.4,8,10

O tratamento não medicamentoso da dislipidemia deve englobar modificações de hábitos alimentares e atividade física, além da perda ponderal, quando indicada.10 Na abordagem nutricional, deve-se limitar a ingestão de ácidos graxos saturados e trans assim como de colesterol, além aumentar a ingestão de fibras solúveis. O consumo de fitosteróis também está indicado no tratamento da hipercolesterolemia, segundo várias diretrizes e consensos de diferentes sociedades em todo o mundo.4,5,8,10-12 Existem evidências consistentes de que a ingestão de fitosteróis (2 g/dia) está associada a uma redução significativa do LDL-C (8-10%).11 Entretanto, não existem dados indicando que o consumo de fitosteróis possa reduzir o risco de DCV. Pelo contrário, alguns estudos sugerem que a elevação concomitante na concentração plasmática de fitosteróis pode aumentar o risco de desenvolvimento de aterosclerose.13,14

Esta revisão tem como objetivo abordar as evidências disponíveis na literatura sobre a relação entre fitosteróis e risco de DCV.

Fitosteróis Definição, classificação e fontes alimentares

O termo "fitosteróis" é utilizado para descrever os esteróis vegetais e seus derivados saturados, os estanóis vegetais.15,16 Os fitosteróis são compostos bioativos encontrados naturalmente em alimentos de origem vegetal e apresentam estrutura química similar à do colesterol,17 que é encontrado apenas em alimentos de origem animal. Mais de 250 fitosteróis já foram identificados.15 Os esteróis vegetais mais comuns na dieta são o beta-sitosterol, o campesterol e o estigmasterol. Já em relação aos estanóis vegetais, o beta-sitostanol e o campestanol são os dois tipos mais comuns.18

As fontes alimentares de fitosteróis incluem os óleos vegetais, especialmente de milho (909 mg/100 mL), girassol (411 mg/100 mL), soja (320 mg/100 mL) e oliva (300 mg/100 mL); as frutas oleaginosas como amêndoas (183 mg/100 g); cereais como gérmen de trigo (344 mg/100 g) e farelo de trigo (200 mg/100 g); além de frutas e hortaliças, como maracujá (44 mg/100 g), laranja (24 mg/100 g) e couve-flor (40 mg/100 g).18 Uma dieta ocidental típica contém cerca de 300 mg de esteróis e 30 mg de estanóis vegetais,17 enquanto dietas vegetarianas podem alcançar um teor mais elevado (300-500 mg/dia).18 Esta quantidade de fitosteróis presente em uma dieta habitual é considerada pequena para se alcançar a ingestão diária recomendada de fitosteróis capaz de apresentar efeitos terapêuticos na redução do LDL-C (~2 g/dia), sendo em geral necessário o consumo de alimentos enriquecidos com fitosteróis ou, então, o uso de suplementos de fitosteróis.16,18 No Brasil, estão disponíveis alguns alimentos industrializados enriquecidos com fitosteróis, incluindo margarina, iogurte e leite.

 Mecanismo de ação sobre o colesterol

O principal mecanismo pelo qual os fitosteróis diminuem os níveis de LDL-C é através da redução (30-50%) na absorção intestinal de colesterol.15,16 Essa redução pode ser mediada por alguns mecanismos, dentre os quais se destaca a competição com o colesterol pela solubilização nas micelas mistas na luz intestinal, diminuindo a quantidade de colesterol disponível para absorção.15,19 Outros mecanismos propostos incluem: (1) modificação na expressão dos genes que codificam as proteínas transportadoras de esteróis, como a proteína Niemann-Pick C1-like 1 (NPC1-L1), reduzindo o transporte de colesterol para o enterócito ou transportadores cassete de ligação a ATP (ABCG5 e ABCG8), promovendo o efluxo de colesterol dos enterócitos para o lúmen intestinal; (2) redução na taxa de esterificação do colesterol no enterócito; e (3) aumento na remoção de colesterol do organismo através da excreção transintestinal de colesterol (TICE).17 Em resposta à redução na absorção de colesterol dietético, a síntese hepática de colesterol parece aumentar, porém o aumento na liberação hepática de colesterol não é suficiente para compensar a menor absorção de colesterol dietético.16

A absorção intestinal dos esteróis (< 2%) e estanóis vegetais (< 0,2%) é bem menor do que a do colesterol (~50%).17 Como resultado da baixa absorção e eficiente excreção biliar após captação hepática, os níveis circulantes de fitosteróis são muito baixos, variando de 0,3 a 1,0 mg/dL para os esteróis e de 0,002 a 0,012 mg/dL para os estanóis vegetais. A distribuição dos fitosteróis através das principais classes de lipoproteínas é similar à do colesterol, portanto, circulam principalmente nas partículas de LDL (65 - 70%).11

Efeito hipocolesterolemiante dos fitosteróis

Desde a década de 1950, inúmeros estudos indicam de forma consistente que os alimentos enriquecidos com fitosteróis reduzem as concentrações de LDL-C.20-24 A Tabela 1 mostra alguns ensaios clínicos randomizados e placebo-controlados publicados desde 2010 que avaliaram os efeitos de alimentos enriquecidos com fitosteróis sobre a colesterolemia. Nessa tabela, pode-se observar que a dose utilizada é em torno de 2 - 4 g/dia e a redução no LDL-C é de ~10%. Por exemplo, o estudo de Párraga-Martínez et al.,25 avaliou a ingestão de 2 g/dia de estanóis vegetais durante 12 meses e observou redução de 11% nos níveis de LDL-C. Já o estudo de Vásquez-Trespalacios & Romero-Palacio26 avaliou a ingestão de 4 g/dia de estanóis vegetais e observou após 4 semanas diminuição de 10,3% nos níveis LDL-C. Dentre os estudos listados na Tabela 1, o estudo que utilizou a maior dose de fitosteróis (8,8 g/dia de estanóis vegetais) foi o realizado por Gylling et al.,27 que observou redução de 17,1% nos níveis de LDL-C.

Ensaios clínicos randomizados avaliando os efeitos da suplementação de fitosteróis sobre a colesterolemia
Autores (ano) n Tipo de fitosterol (alimento/suplemento) Dose de fitosterol (g/dia) Duração ↓ LDL-C (%) Valor de p (versus grupo controle)
Estudos com alimentos enriquecidos com fitosteróis
Gylling et al. (2010)27 49 indivíduos com hipercolesterolemia leve a moderada Estanóis (spread e bebida) 8,8 10 semanas 17,1 0,01
Gylling et al.(2013)39 92 indivíduos assintomáticos (sem uso de drogas hipolipemiantes) Estanóis (spread) 3 6 meses 10,2 0,001
Buyuktuncer et al. (2013)40 70 indivíduos com hipercolesterolemia leve a moderada Estanóis (iogurte) 1,9 4 semanas 6,3 0,005
Vásquez-Trespalacios & Romero-Palacio (2014)26 40 indivíduos com hipercolesterolemia moderada Estanóis (iogurte) 4 4 semanas 10,3 < 0,01
Ras et al. (2015)41 240 indivíduos com hipercolesterolemia Esteróis (spread) 3 12 semanas 6,7 < 0,05
Párraga-Martinez et al. (2015)25 182 adultos com hipercolesterolemia Estanóis (iogurte) 2 12 meses 11 0,01
Estudos com cápsulas ou comprimidos
Maki et al. (2012)32 32 indivíduos com hipercolesterolemia primária Esteróis/Estanóis (comprimido) 1,8 6 semanas 4,9 < 0,05
Maki et al. (2013)29 28 indivíduos com hipercolesterolemia primária Esteróis/Estanóis (cápsula softgel) 1,8 6 semanas 9,2 < 0,001
Ottestad et al. (2013)30 41 indivíduos com colesterol total de 180 – 300 mg/dL Esteróis/Estanóis (cápsula softgel) 2 4 semanas 2,7 0,32
McKenney et al. (2014)31 30 adultos com hipercolesterolemia familiar Esteróis/Estanóis (cápsula softgel) 1,8 6 semanas 4,3 < 0,01

LDL-C: colesterol da lipoproteína de baixa densidade.

Metanálises recentes confirmam o efeito hipocolesterolemiante dos fitosteróis, além de compararem efeitos dos esteróis com os dos estanóis e avaliarem a relação dose-resposta.21-24 A relação dose-resposta apresentou discreta variação entre as metanálises, e ainda não há um consenso. Uma metanálise conduzida por Ras et al.,24 incluiu 124 estudos com dose média de fitosteróis de 2,1 g/dia (variação de 0,2 a 9,0 g/dia). A ingestão de 0,6 - 3,3 g/dia esteve associada com uma redução gradual na concentração do LDL-C de 6 - 12%. Os esteróis e estanóis vegetais apresentaram efeitos comparáveis. Os estudos com doses excedendo 4 g/dia não foram agrupados, pois eram poucos e apresentavam doses muito variadas. Os autores concluíram que o efeito redutor do LDL-C tanto dos esteróis quanto dos estanóis vegetais aumentam até uma ingestão de cerca de 3 g/dia, com um efeito médio de 12%.24 Uma metanálise realizada por Talati et al.,22 comparou os efeitos dos esteróis e estanóis vegetais sobre o LDL-C e também não observou diferenças significativas.

Os dados indicando o efeito hipocolesterolemiante dos alimentos enriquecidos com fitosteróis são provenientes de estudos de intervenção com boa qualidade metodológica realizados com um número relativamente grande de participantes e, de uma forma geral, os resultados são consistentes.28 De acordo com as principais sociedades científicas internacionais, o uso regular de 2 g/dia de fitosteróis sob supervisão pode ser recomendado para redução de 10% no nível de LDL-C.4,5,8,10-12

Saindo um pouco do cenário dos alimentos enriquecidos, alguns estudos recentes avaliaram os efeitos dos fitosteróis em comprimidos ou cápsulas,29-32 com objetivo de avaliar se esta forma de suplementação (considerada mais prática por muitos autores) também seria efetiva na redução do colesterol. O estudo de Maki et al.,29 utilizou cápsulas de softgel, fornecendo 1,8 g/dia de esteróis/estanóis esterificados em conjunto com modificações no estilo de vida recomendadas pelo National Cholesterol Education Program (NCEP) durante 6 semanas e observou redução de 9,2% nos níveis do LDL-C. Uma redução significativa do LDL-C também foi observada nos estudos conduzidos por Maki et al.,32 e McKenney et al.,31 Entretanto, o estudo conduzido por Ottestad et al.,30 não observou redução significativa nos níveis de LDL-C. Uma metanálise recente33 incluindo oito estudos publicados de 1992 a 2013 com duração de 4-6 semanas e doses de fitosteróis entre 1 a 3 g/dia em comprimidos ou cápsulas observou uma redução significativa do LDL-C (em média 12 mg/dL), que foi semelhante à observada com alimentos enriquecidos com fitosteróis. Portanto, apesar de ainda não haver um consenso, a maioria dos estudos indica que o uso de fitosteróis em comprimidos ou cápsulas pode ser efetivo na redução dos níveis de LDL-C.

Existem evidências de que o consumo de fitosteróis em associação com terapia medicamentosa hipolipemiante é capaz de promover redução adicional do colesterol sérico. Tais benefícios já foram observados em associação com estatinas34-36 e também com ezetimiba.37,38 A metanálise elaborada por Han et al.,36 incluiu 15 ensaios clínicos randomizados que avaliaram os efeito de dietas enriquecidas com fitosteróis em pacientes em uso de estatinas. Os fitosteróis em combinação com as estatinas, em comparação com estatinas isoladamente, produziram redução significativa no LDL-C de 12 mg/dL.

 Fitosteróis e doença cardiovascular

A relação direta entre ingestão de alimentos enriquecidos com fitosteróis e o risco de DCV ainda não foi investigada em ensaios clínicos randomizados. Já foi estimado que seria necessário o acompanhamento de pelo menos 33.000 indivíduos durante cerca de 10 anos para se avaliar de forma adequada os efeitos dos fitosteróis sobre desfechos duros (hard endpoints), tornando tais estudos pouco viáveis.42

Por inferência com base na eficácia cardioprotetora de outras intervenções hipocolesterolemiantes, alguns autores consideram que os fitosteróis podem reduzir o risco cardiovascular; porém, esta afirmação não deve ser realizada até que estudos comprovando tal fato estejam disponíveis.43

- Níveis séricos de fitosteróis

A especulação em relação a um potencial efeito deletério dos fitosteróis foi, em grande parte, motivada pelo fato da fitosterolemia (também conhecida como sitosterolemia), uma doença autossômica recessiva rara, ser caracterizada por um aumento de 50 vezes na concentração circulante de esteróis vegetais e estar associada com aterosclerose precoce. Entretanto, o consumo de alimentos enriquecidos com fitosteróis está associado com aumento muito menor (em torno de 2 vezes) nos esteróis vegetais circulantes.44

Vários estudos já avaliaram a associação entre concentração plasmática de fitosteróis e DCV, porém os resultados são discordantes. Alguns estudos encontraram associação positiva entre os níveis séricos de fitosteróis (ou na relação fitosteróis/colesterol) e risco de DCV;13,14 enquanto outros não observaram associação ou até mesmo encontraram associação inversa.45-47 Genser et al.,48 publicaram uma revisão sistemática e metanálise baseada em 17 estudos envolvendo 11.182 indivíduos e não observaram evidência de associação entre concentração sérica de fitosteróis e desenvolvimento de DCV. Os autores desta metanálise atribuíram a grande divergência nos resultados dos estudos aos diferentes desenhos de estudos e ajustes para potenciais variáveis de confundimento. Eles sugerem que vieses podem ocorrer se os investigadores não realizam ajustes adequados, principalmente para os níveis séricos das lipoproteínas, em especial para o LDL-C.48 Outra possibilidade é o fato dos fitosteróis circulantes por si só não aumentarem o risco de DCV, mas sim serem apenas marcadores da absorção de colesterol.49

- Marcadores intermediários de risco cardiovascular

Devido à ausência de estudos avaliando desfechos cardiovasculares, a investigação de marcadores intermediários de risco para DCV representa uma forma aceitável e viável para se avaliar a relação entre fitosteróis e risco cardiovascular. Atualmente, estão disponíveis estudos avaliando disfunção endotelial, rigidez arterial, diâmetro dos vasos da retina e inflamação de baixo grau.39,41,50-54

No estudo realizado por Gylling et al.,39 o consumo de estanóis (3 g/dia) durante 6 meses apresentou efeitos benéficos sobre a rigidez arterial, especialmente em homens. Além disso, a função endotelial, avaliada por tonometria arterial periférica, melhorou com a redução do LDL-C e do colesterol não da lipoproteína de alta densidade (não-HDL). No estudo conduzido por Heggen et al.,52 foram testados os efeitos de duas margarinas ricas em esteróis vegetais (2 g/dia) provenientes de dois óleos vegetais distintos durante 4 semanas. Os autores observaram redução significativa da E-selectina e do inibidor do ativador do plasminogênio 1 (PAI-1) total com a ingestão de apenas uma das margarinas. Neste estudo não foi observada redução significativa da molécula de adesão celular vascular 1 (VCAM-1) e do fator de necrose tumoral a (TNF-α) com nenhuma das margarinas e também não foi observada associação entre redução do LDL-C e modificações na E-selectina e no PAI-1 total.52

Por outro lado, a suplementação com 3 g/dia de esteróis vegetais durante 12 semanas em 240 indivíduos com hipercolesterolemia não resultou em efeitos benéficos sobre a rigidez arterial e função endotelial.41,54 Neste estudo, a função endotelial foi avaliada por dilatação fluxo-mediada41 e biomarcadores circulantes: molécula de adesão intercelular 1 (ICAM-1), VCAM-1 e E-selectina.54

Em dois ensaios clínicos cruzados realizados com crianças com hipercolesterolemia familiar, o consumo de fitosteróis durante 4 semanas não melhorou a função endotelial avaliada por dilatação fluxo-mediada, apesar de ter induzido redução significativa do LDL-C.50,51

No ensaio clínico randomizado realizado por Kelly et al.,53 foram avaliados os efeitos do consumo a longo prazo (85 semanas) de esteróis e estanóis vegetais sobre o diâmetro dos vasos da retina (microcirculação). Foram incluídos no estudo três grupos de pacientes que consumiram margarina enriquecida com esteróis vegetais (2,5 g/dia), margarina enriquecida com estanóis vegetais (2,5 g/dia) e margarina sem fitosteróis. Não foram observadas modificações significativas no diâmetro venular nos três grupos, porém as modificações na concentração sérica de campesterol (um tipo de esterol vegetal) se associaram positivamente com as modificações no diâmetro venular, independentemente do nível de LDL-C (r = 0,39, p = 0,03).

Em relação à inflamação, não foi observada redução significativa em nenhum dos marcadores avaliados no estudo conduzido por Ras et al.,54: proteína C reativa (PCR), amiloide sérico A, interleucina (IL)-6, IL-8, TNF-α e ICAM-1. Em uma revisão sistemática e metanálise publicada recentemente, Rocha et al.,55 avaliaram o efeito do consumo de fitosteróis sobre marcadores inflamatórios, em especial a PCR. Foram incluídos 20 ensaios clínicos randomizados (n = 1.308) envolvendo alimentos enriquecidos com fitosteróis como tratamento ativo. A redução na concentração de PCR com o consumo de fitosteróis foi de 0,10 mg/dL, não tendo alcançado significância estatística.55

Os resultados desses estudos que avaliaram os efeitos dos fitosteróis sobre marcadores intermediários de risco cardiovascular não observaram efeitos benéficos consistentes. Sendo assim, atualmente não existem evidências de que o uso de fitosteróis possa reduzir o risco de DCV através da atuação sobre esses marcadores.

 - Ingestão de fitosteróis oxidados

Publicações recentes têm alertado para outro potencial efeito deletério dos fitosteróis: a ingestão de fitosteróis oxidados. Os esteróis vegetais (mas não os estanóis, pois são saturados), podem sofrer oxidação formando fitosteróis oxidados e, em analogia ao observado com o colesterol oxidado, acredita-se que essas substâncias podem ser aterogênicas.56 Entretanto, nos estudos com humanos ainda não existe consenso se a ingestão de alimentos enriquecidos com esteróis é capaz de elevar a concentração sérica de fitosteróis oxidados. Por exemplo, no ensaio clínico randomizado e cruzado realizado por Baumgartner et al.,57 43 indivíduos saudáveis consumiram durante 4 semanas margarina enriquecida com esteróis (3 g/dia), margarina enriquecida com estanóis (3 g/dia) e uma margarina controle. O consumo da margarina enriquecida com esteróis não aumentou a concentração sérica de fitosteróis oxidados.57 Outro estudo realizado pelo mesmo grupo58 investigou os efeitos da ingestão de esteróis sobre a concentração de fitosteróis oxidados durante o período pós-prandial. Neste estudo, os indivíduos consumiram uma bebida contendo nenhuma quantidade ou 3 g de esteróis ou de estanóis vegetais. Amostras de sangue foram coletadas até 8 h e após 4 h, os indivíduos receberam uma segunda bebida (sem esteróis ou estanóis). A concentração de fitosteróis oxidados aumentou de forma significativa após o consumo da refeição com esteróis em comparação à refeição com estanóis e a controle. Esse aumento foi observado apenas após o consumo da segunda bebida e os autores concluíram que ainda não se sabe se o aumento dos fitosteróis oxidados no período pós-prandial seria devido à absorção ou formação endógena. Portanto, até o presente momento, ainda não existe um consenso sobre o papel dos fitosteróis oxidados no desenvolvimento de DCV.

 Fitosteróis e vitaminas lipossolúveis

Considerando-se que os fitosteróis reduzem a absorção intestinal de colesterol, é razoável se imaginar que essas substâncias também possam reduzir a absorção de vitaminas e antioxidantes lipossolúveis. Os níveis séricos das vitaminas A, D e K1 em geral não são afetados pelo consumo de fitosteróis.59 Entretanto, alguns estudos sugerem que os fitosteróis possam promover uma redução modesta na concentração plasmática de carotenoides (principalmente o β-caroteno, α-caroteno e licopeno)27,60 e tocoferóis,61 porém outros estudos não observaram tal fato.62,63 Uma metanálise publicada recentemente avaliou os efeitos do consumo de fitosteróis nas concentrações plasmáticas de vitaminas lipossolúveis e carotenoides. Foram incluídos 41 ensaios clínicos randomizados (n = 3.306) com ingestão média de 2,5 g/dia de fitosteróis. Nas análises ajustadas para o colesterol total, a redução na concentração dos carotenoides hidrocarbonados (β-caroteno, α-caroteno e licopeno) e de alguns carotenoides oxigenados (zeaxantina e criptoxantina) foi significativa. Entretanto, não foi observada redução significativa na concentração do tocoferol, vitamina D, ou retinol. Um achado muito importante desta metanálise é que a concentração dessas substâncias permaneceu dentro da faixa da normalidade, não havendo indicação de que as reduções observadas possam ter implicações negativas sobre a saúde.64 Noakes et al.,65 demonstraram que é possível evitar reduções nas concentrações plasmáticas de carotenoides durante o consumo de fitosteróis através do aumento no consumo diário de frutas e hortaliças ricas em carotenoides.

 O consumo de fitosteróis é seguro?

Ainda não estão disponíveis estudos com acompanhamento a longo prazo que possam garantir a segurança do consumo regular de produtos enriquecidos com fitosteróis, conforme salientado em publicações recentes da European Society of Cardiology / European Atherosclerosis Society12 e da American Heart Association / American College of Cardiology.66 Entretanto, com base na ausência de efeitos adversos em estudos de curta duração e estudos experimentais, diversos autores consideram que o consumo de fitosteróis seja seguro, podendo ser indicado para redução do colesterol inclusive em associação com terapia farmacológica.11,59,63,67,68 Além disto, diferentes sociedades científicas recomendam sua utilização no tratamento da hipercolesterolemia.4,5,8,10-12,28 É importante ressaltar que a suplementação de fitosteróis é contraindicada para os raros pacientes que apresentam fitosterolemia (ou sitosterolemia).16,67

A adição de fitosteróis como ingrediente redutor do colesterol a alimentos industrializados já foi aprovada por várias agências reguladoras em todo o mundo incluindo a Health Canada, U.S. Food and Drug Administration (FDA), European Food and Safety Authority (EFSA), Food Standards Australia New Zealand (FSANZ)16 e Agência Nacional de Vigilância Sanitária (ANVISA) no Brasil.69

Segundo a ANVISA, os alimentos enriquecidos com fitosteróis podem conter a seguinte alegação no rótulo: "Os fitosteróis auxiliam na redução da absorção de colesterol. Seu consumo deve estar associado a uma alimentação equilibrada e hábitos de vida saudáveis". A ANVISA determina que para conter tal alegação, a porção do produto pronto para consumo deve fornecer no mínimo 0,8 g de fitosteróis livres. Além disto, no rótulo desses produtos deve constar frases como: "O produto não é adequado para crianças abaixo de 5 anos, gestantes e lactantes".69

Considerações finais

O consenso sobre fitosteróis da European Atherosclerosis Society publicado recentemente concluiu que com base no efeito redutor do LDL-C e na ausência de sinais adversos, o consumo de alimentos enriquecidos com fitosteróis pode ser considerado: (1) em indivíduos com hipercolesterolemia apresentando risco cardiovascular intermediário ou baixo que não possuem indicação de farmacoterapia, (2) como adjuvante da terapia farmacológica em pacientes com risco cardiovascular elevado e muito elevado que não conseguem alcançar os objetivos de LDL-C com estatinas ou são intolerantes às estatinas e (3) em adultos e crianças (> 6 anos) com hipercolesterolemia familiar juntamente com modificações no estilo de vida e terapia medicamentosa.11

A grande maioria das diretrizes e consensos para tratamento da dislipidemia e/ou prevenção de DCV recomenda a ingestão de fitosteróis na quantidade de aproximadamente 2 g/dia com o objetivo de reduzir o LDL-C em cerca de 10% em associação com modificações no estilo de vida.4,5,8,10-12,28

Atualmente, o conhecimento sobre a relação entre consumo de fitosteróis e risco de DCV é incompleto. As evidências disponíveis não confirmam se os fitosteróis conferem proteção cardiovascular e também não comprovam efeitos deletérios. Há necessidade de novos estudos, principalmente com a suplementação de fitosteróis a longo prazo.

Fontes de financiamento

O presente estudo não teve fontes de financiamento externas.

Vinculação acadêmica

Este artigo é parte do trabalho de conclusão de Residência em Nutrição Clínica de Carlos Eduardo Cabral pela Universidade do Estado do Rio de Janeiro.