IngredientesSitostanol, also known by its systematic botanical-chemical name stigmastanol, is a fully saturated phytostanol belonging to the broad class of phytosterols — plant-derived sterol compounds structurally analogous to cholesterol in animals. Its IUPAC systematic name is 3β,5α-stigmastan-3-ol, and it carries CAS Number 83-45-4. It is also sometimes referred to in literature as β-sitostanol or 5α-sitostanol.
While cholesterol is the predominant sterol in animal cells, plant membranes contain little or no cholesterol; instead they contain several phytosterols, structurally similar to cholesterol but with a methyl or ethyl group at C-24 and one or two carbon-carbon double bonds. Sitostanol is a fully saturated subgroup of phytosterols with no double bonds.
Specifically, 5α-sitostanol is the saturated form of sitosterol and stigmasterol. The sterols are unsaturated, having a double bond between C4 and C5 positions in the steroid nucleus, like cholesterol, whereas stanols are 5α-saturated after addition of hydrogen atoms, missing that double bond.
Stigmastanol (sitostanol) is the product of the reduction of β-sitosterol and the hydrogenation of stigmasterol. In terms of broader chemical taxonomy, phytosterols, and by extension phytostanols, are chemically classified as triterpenes, a class of terpenes composed of six isoprene units.
Phytosterols are nonnutritive compounds (or phytochemicals) with the same basic functions in plants as cholesterol in animals — that is, they regulate the membrane fluidity of plant cells and other physiologic functions associated with plant biology. Their chemical structure differs from that of cholesterol because of additional alkyl substituents at C-24 and/or a double bond at C-22.
Stanols are saturated sterols with no double bonds in the sterol ring and are less abundant in nature than the sterols. Sitostanol's parent compound, β-sitosterol, belongs to the group of 4-desmethyl sterols — the most frequently encountered phytosterols — which on average account for approximately 65% of dietary phytosterol intake.
Stigmastanol (sitostanol) is a phytosterol found in a variety of plant sources. As a saturated stanol, it occurs in nature in considerably lower concentrations than its unsaturated sterol precursors.
Phytosterols and phytostanols are present in vegetable foods, especially in vegetable oils (corn oil, rapeseed (canola) oil, soybean oil, and sunflower oil), nuts, seeds, and cereals. The main food sources for phytosterols are vegetable oils, vegetable-fat spreads and margarines, nuts, cereals and cereal products (bread), and vegetables. The main food sources for phytostanols specifically are cereals, especially wheat and rye. The most abundant phytosterols and phytostanols in the human diet are sitosterol, campesterol, sitostanol, and campestanol.
Phytostanols are completely saturated forms of phytosterols and lack the carbon–carbon double bonds found in cholesterol and phytosterols. Typical dietary consumption of stanols is approximately 25 mg/day, derived primarily from corn, wheat, rye, and rice.
A particularly notable natural source is corn fiber oil. Corn fiber oil contains a high level of sitostanol in the ferulic acid ester fraction and appears to be the richest source of natural stanols (and stanol esters) ever reported. The major product of hydrogenation, sitostanol, also occurs naturally in corn fiber oil and is of predominant use in Northern Europe, providing an effective alternative to phytosterols in products affecting cholesterolemia.
Regarding dietary intake from natural sources alone, daily intake of total stanols in the Finnish diet has been estimated at 30–80 mg/day; however, tall oil sterols (sterols from pine trees) contain 10–20% of plant stanols (sitostanol plus campestanol).
For commercial production, commercially, phytosterols are isolated from vegetable oils such as soybean oil, rapeseed (canola) oil, sunflower oil, or corn oil, or from "tall oil," a by-product of the manufacture of wood pulp. Phytosterols can then be hydrogenated to obtain phytostanols. The stanols from wood were developed at universities in Finland and commercialized as Benecol. Sitosterol is a product of the wood industry, which is saturated to form sitostanol.
Sitostanol is commercially available and consumed in several distinct forms, each with differing physical properties and bioavailability characteristics.
Phytostanol esters are chemically stable materials, having comparable chemical and physical properties to edible fats and oils.
Sitostanol itself does not possess a traditional or ethnopharmacological history of use as an isolated compound; it was identified and studied as part of the broader class of phytosterols in the context of modern nutritional science. However, the history of phytosterols and their saturated derivatives in medicine and nutrition is well-documented from the mid-twentieth century onward.
The plasma cholesterol-lowering properties of plant sterols have been known since the 1950s (Pollak, 1953). Early studies examined the cholesterol-reducing potential of plant sterols using up to 25 g/day consumed in solid crystalline form.
The cholesterol-lowering properties of phytosterols were first demonstrated approximately 50 years ago by Peterson, who fed chicks plant sterols in their diet. Shortly thereafter, Pollak showed the same effect in humans, to whom he administered crude sitosterol 5 to 10 g/day for up to 8 months. In similar studies in rabbits, Pollak observed that sitosterol was poorly absorbed and that if present in excess, it blocked the absorption of cholesterol and prevented atherosclerosis.
The plant sterol sitosterol was first described as a therapeutic agent for hypercholesterolaemia in 1951. In the late 1950s, Eli Lilly Company introduced the first plant sterol product, 'Cytellin', as a cholesterol-lowering pharmaceutical. From the 1950s to the 1980s, a preparation of predominantly β-sitosterol [Cytellin, Eli Lilly] was marketed in the USA to treat hypercholesterolaemia. The first commercial phytosterol preparation for cholesterol lowering was introduced by the Eli Lilly Company in the 1950s; the preparation initially contained about 65% sitosterol, but later preparations contained up to 90% sitosterol.
Plant sterols have been the subject of numerous high-dose (up to 25 g/day), long-term clinical trials to assess their effects on blood cholesterol levels, with over 1,800 people in total having participated in these studies, conducted since the early 1950s.
The specific use of sitostanol — the fully saturated derivative — to lower plasma cholesterol was a later development, arising from research demonstrating the superior cholesterol-inhibiting properties of stanols over sterols. The first description of the use of plant stanols to lower plasma cholesterol was by Heinemann et al. in 1986. The investigators showed that administration of capsules of sitostanol dispersed in sunflower oil at a dose of 1.5 g/day lowered LDL cholesterol by 15% in hypercholesterolaemic adults; plasma sitostanol levels were undetectable during the study in most individuals.
A pivotal development was the esterification of sitostanol to improve its fat-solubility. This process was patented by the Finnish company Raisio Group, Raisio, Finland, in 1989, and resulted 6 years later in their marketing Benecol margarine. This led to the launch of Benecol (margarine; Raisio Group, Raisio, Finland) in 1995. The coincident publication of the year-long North Karelia study conclusively demonstrated the long-term LDL-lowering efficacy of plant stanol esters.
Sitostanol's biological activity is rooted in its structural similarity to cholesterol combined with important differences that prevent its own significant absorption. Both plant sterols and plant stanols differ from cholesterol only in the side chain attached to the sterol ring. Plant stanols are saturated plant sterols without a double bond in the sterol ring. Due to their saturation status, plant stanols are less effectively absorbed.
The primary and best-established mechanism of action of sitostanol is competitive inhibition of intestinal cholesterol absorption. The cholesterol-lowering action of phytosterols/phytostanols is thought to occur, at least in part, through competition with dietary and biliary cholesterol for intestinal absorption in mixed micelles.
Phytosterols and phytostanols lower LDL cholesterol by displacing cholesterol from mixed micelles in the small intestine so that cholesterol absorption is partially inhibited.
Plant sterols/stanols are taken up from the intestinal lumen into the enterocyte in the same way as cholesterol by a sterol transporter, Niemann-Pick C1-Like 1 (NPC1L1). From the enterocyte, however, most of the plant sterols/stanols are pumped back to the intestinal lumen and out of the body by the ATP-binding cassette transporters ABCG5 and ABCG8.
Under normal physiological conditions, nearly all absorbed phytosterols are excreted in bile via adenosine triphosphate–binding cassette subfamily G member 5 and 8 (ABCG5/8) transporters, with less than 5% retained.
Recent evidence also suggests that phytosterols/phytostanols may regulate proteins implicated in cholesterol metabolism both in enterocytes and hepatocytes, and important advances in understanding intestinal sterol absorption have provided potential molecular targets of phytosterols.
Sitostanol demonstrates superior cholesterol absorption inhibition compared to its unsaturated precursor, sitosterol. The effects of two different plant sterols on intestinal cholesterol absorption were compared in normal volunteers by an intestinal perfusion study. Cholesterol absorption during the control period averaged 32 ± 11% for the sitosterol group and 29 ± 9% for the sitostanol group. Following a high dose of sitosterol, absorption was reduced to approximately 16%, while the same dose of sitostanol reduced cholesterol absorption significantly to 5.1 ± 2.9%. Overall, cholesterol absorption declined during sitosterol infusion by almost 50%, whereas sitostanol infusion caused a reduction of cholesterol absorption by almost 85%.
Sitostanol is virtually unabsorbed and lowers the cholesterol content of mixed micelles more efficiently than sitosterol, thus showing an enhanced serum cholesterol-lowering effect.
Studies of the metabolism of cholesterol have shown that sitosterol (and by extension, sitostanol) inhibits the absorption of both endogenous and dietary cholesterol from the intestines. As a result of this, the excretion of neutral steroids in the stools increases, which leads to a shortage of cholesterol in the liver and through that to a decreased serum cholesterol level.
The decrease in plasma cholesterol is probably due to an increase in LDL receptor activity. However, the decline in plasma cholesterol is relatively less than the decrease in absorption, presumably because of a compensatory increase in cholesterol synthesis.
Animal studies also suggest that sitostanol inhibits biosynthesis of cholesterol in the liver.
The cardiovascular lipid-lowering effect of sitostanol and its ester preparations is the most extensively studied and robustly supported area of research. The body of evidence spans decades, multiple population groups, and numerous clinical trial designs, ultimately converging in several major meta-analyses.
The pivotal clinical milestone came in 1995 with the North Karelia study. Results from this large-scale, 12-month randomised double-blind study show that a daily intake of 1.8–2.6 g of fat-soluble sitostanol ester (calculated as free stanol) administered in a margarine decreased total cholesterol by 10% and LDL cholesterol by 14% compared to the reference group having a margarine without added fat-soluble stanol ester.
Miettinen et al. (1995) demonstrated for the first time that foods such as margarine enriched with sitostanol ester lowered both total serum cholesterol and LDL-C in mildly hypercholesterolaemic subjects. Subsequent data show consistent support for the LDL-C lowering effects of foods with added plant sterols/stanols.
A meta-analysis of 59 eligible randomised clinical trials published from 1992 to 2006 identified from five databases calculated weighted mean effect sizes for net differences in LDL levels using a random-effects model. Plant sterol-containing products decreased LDL levels by 0.31 mmol/L (95% CI: –0.35 to –0.27, P < 0.0001) compared with placebo. Between-trial heterogeneity was evident, indicating that observed differences between trial results were unlikely to have been caused by chance.
Reductions in LDL levels were greater in individuals with high baseline LDL levels compared with those with normal to borderline baseline LDL levels.
A dose-response meta-analysis comparing stanols and sterols found important differences in maximal efficacy. The maximal LDL-CH reductions for plant stanols (16.4%) and plant stanol esters (17.1%) were significantly greater than the maximal LDL-CH reductions for plant sterols (8.3%) and plant sterol esters (8.4%). These findings persisted in several additional analyses. Intakes of plant stanols in excess of the recommended 2 g/day dose are associated with additional and dose-dependent reductions in LDL-CH, possibly resulting in further reductions in the risk of coronary heart disease.
A broad, population-independent summary of the evidence from a peer-reviewed review article confirmed: the efficacy of phytosterols and phytostanols added to foods and food supplements to obtain significant non-pharmacologic serum and LDL cholesterol reduction is well documented. Irrespective of age, gender, ethnic background, body weight, background diet, or the cause of hypercholesterolaemia, and even added to statin treatment, phytosterols and phytostanols at 2 g/day significantly lower LDL cholesterol concentration by 8–10%. They do not affect the concentrations of high-density lipoprotein cholesterol, lipoprotein (a), or serum PCSK9. In some studies, phytosterols and phytostanols have modestly reduced serum triglyceride levels especially in subjects with slightly elevated baseline concentrations.
Plant sterols/stanols (when taken at 2 g/day) cause significant inhibition of cholesterol absorption and lower LDL-C levels by between 8 and 10%.
Initial impressions were that stanols were more effective and safer than sterols, but the negative outcome of a study led to the recognition that the lipid solubility of free stanols was very limited. This was overcome by esterifying them with fatty acids, with the resultant stanol esters being freely soluble in fat spreads.
With the development of techniques for solubilising plant sterols in fats, it became apparent that much lower doses of plant sterols were required to reduce serum cholesterol when the material was solubilised in margarine.
Sitostanol has an additive effect with the statins in lowering LDL cholesterol.
Even added to statin treatment, phytosterols and phytostanols at 2 g/day significantly lower LDL cholesterol concentration by 8–10%. This additive effect is mechanistically explicable: statins reduce hepatic cholesterol synthesis, while sitostanol reduces intestinal cholesterol absorption — complementary pathways.
The lessons from the IMPROVE-IT study demonstrated that reducing cholesterol absorption by approximately 40% with ezetimibe when added to statin treatment diminished LDL-C concentration by 24% and decreased the vascular event rate by 6.4% compared to the statin-only group. Phytosterol consumption of 2 g/day reduces cholesterol absorption by the same amount as ezetimibe.
Two studies showed an LDL cholesterol reduction of about 15% in children with familial hypercholesterolaemia treated with stanol esters, which compares favourably with the 8% reduction in children with average levels of LDL cholesterol.
Data indicate that sitostanol, even with a dose four-fold lower than that of sitosterol, was significantly more effective in reducing elevated levels of low-density lipoprotein cholesterol, and the reduction in serum lipid levels was of the same magnitude as that observed with systemic lipid-lowering drugs. These results suggest that sitostanol, a non-absorbable plant sterol, could be the drug of choice for treating familial hypercholesterolaemia in childhood.
A meta-analysis of 41 trials showed that intake of 2 g/day of stanols or sterols reduced LDL by 10%; higher intakes added little. Efficacy is similar for sterols and stanols, but the food form may substantially affect LDL reduction. Effects are additive with diet or drug interventions: eating foods low in saturated fat and cholesterol and high in stanols or sterols can reduce LDL by 20%.
These results demonstrate that dietary sitostanol at a concentration of 0.8% (w/w) or 0.64 g/day lowered plasma cholesterol levels and depressed atherosclerosis development in rabbits (animal study). Plant sterols have been shown to decrease plasma total cholesterol (TC) and LDL-C levels in animals and humans with no known toxicity.
Despite increased serum sitostanol contents during plant stanol ester consumption, arterial levels were unchanged, suggesting that sitostanol is not taken up into the arterial wall.
Importantly, it has not been directly demonstrated in prospective human cardiovascular outcome trials that sitostanol supplementation independently reduces rates of myocardial infarction or cardiovascular death. The evidence for cardiovascular risk reduction is mechanistic and inferential — based on the established relationship between LDL reduction and cardiovascular event reduction. This distinction should be noted when evaluating the strength of evidence.
Phytosterols are present in foods and reduce intestinal cholesterol absorption. Sitostanol, a 5α-reduced metabolite of the common plant sterol sitosterol, is particularly effective.
Previous clinical trials of cholesterol lowering by phytosterols used large doses and yielded variable results. For example, 3–18 g sitosterol/day was found to reduce plasma cholesterol concentrations by only 5–12%. There was marked patient-to-patient variability. A review of 8 clinical phytosterol trials reported LDL-cholesterol reductions varying from 7% to 33%, but a recent well-controlled study failed to find any LDL reduction when 3 g sitostanol/day was used (as free powder, without appropriate solubilization).
These findings underscore that formulation — not just dose — is a critical determinant of efficacy.
Dosage information below is drawn directly from study data; it is not prescriptive.
There is a documented dose–response relationship for stanols above 2 g/day. Intakes of plant stanols in excess of the recommended 2 g/day dose are associated with additional and dose-dependent reductions in LDL-CH, possibly resulting in further reductions in the risk of coronary heart disease.
Plant sterols have been shown to decrease plasma total cholesterol and LDL-C levels in animals and humans with no known toxicity. Early long-term clinical trials with high-dose plant sterols reported no adverse effects. No adverse effects were reported in the Cytellin studies conducted from the 1950s through the 1980s. Dietary sitostanol was virtually undetectable in the plasma of humans and animals under normal (non-sitosterolaemia) conditions, attributable to efficient efflux by ABCG5/G8 transporters.
The most consistently documented safety signal for sitostanol and phytostanols is their potential to reduce circulating concentrations of carotenoids and fat-soluble vitamins. Concerns have been raised regarding the potential of phytosterols to impair absorption and status of fat-soluble vitamins. Particular consideration is given to the observed lowering effect on plasma concentrations of carotenoids, especially β-carotene — in the range of up to 20% decrease observed with ingestion over one year of 20 g/day of products containing 8% phytosterols.
The primary concern regarding phytosterol supplementation is the effect it may have on the absorption and circulating levels of lipid-soluble vitamins and carotenoids. Dietary phytosterols inhibit the absorption of dietary and biliary cholesterol, which in turn decreases the absorption of carotenoids and lipid-soluble vitamins.
However, the clinical significance of this finding remains uncertain. Possible interference with liposoluble vitamins has been hypothesized, with a subsequent reduction in these vitamins' absorption and a reduction of carotenoid plasma levels; however, there is no evidence yet of low carotenoid and vitamin levels due to concomitant plant sterols consumption.
The Scientific Panel on Dietetic Products, Nutrition and Allergies of the EFSA has emphasised the need for risk management measures in order to minimise the likelihood of a daily intake exceeding 3 g phytosterols/phytostanols, and the provision of appropriate information to consumers regarding the need for regular consumption of fruits and vegetables to address the potential beta-carotene lowering effect.
Sitosterolaemia is a rare autosomal recessive genetic disorder that represents the most significant contraindication to sitostanol use. Sitosterolaemia is caused by mutations in the ATP-binding cassette (ABC) cotransporters, either ABCG5 and/or ABCG8, leading to an accumulation of plant sterols in plasma and tissues that, in turn, results in accelerated development of CVD, anemia, platelet defects, and other disorders.
Margarines and other products containing stanols (e.g., campestanol and sitostanol), which are recommended for use by individuals with hypercholesterolaemia, are contraindicated in those with sitosterolaemia as they can exacerbate plant stanol accumulation.
The main real contraindication to plant sterols use is sitosterolaemia, a rare genetic disease with recessive autosomal inheritance caused by a misfunctioning of ABCG5 and ABCG8 and characterised by increased plant sterols absorption and premature atherosclerosis. An increase in sitosterol and LDL-C plasma levels, with consequent increased CHD risk, has also been described in subjects heterozygous for a "loss of function" variant of ABCG5/8: supplementation with plant sterols can be dangerous in this category of subjects as well.
There is a pending question whether elevated serum plant sterols/stanols are atherogenic. It is frequently considered that phytosterolaemia (sitosterolaemia), a rare disease with extremely elevated serum and tissue plant sterol/stanol concentrations resulting from mutations in ABCG5 and ABCG8, presents a clinical example of the atherogenicity of elevated plant sterols/stanols.
In the European Union, plant stanol esters used in Benecol products were granted novel food status under Regulation (EC) No 258/97 in 2000, allowing their incorporation into various food matrices.
Commission Regulation (EC) No 608/2004 concerning the labelling of foods and food ingredients with added free phytosterols, phytosterol esters, phytostanols and/or phytostanol esters laid down labelling requirements and limited the consumption of added phytosterols to a maximum of 3 g per person per day.
The authorised novel food specification for phytosterols/phytostanols must contain less than 81% β-sitosterol, less than 35% β-sitostanol, less than 40% campesterol, less than 15% campestanol, less than 30% stigmasterol, and less than 3% brassicasterol. It should be used as part of a healthy diet, including regular consumption of fruit and vegetables to help maintain carotenoid levels, and consumption of more than 3 g per day should be avoided.
The marketing authorisation lays down labelling requirements indicating the target population — people who want to lower their cholesterol levels — and that patients on cholesterol-lowering medication should only consume these products under guidance, given the potential for additive interactions.
Statin treatment decreases cholesterol synthesis but increases absorption of plant sterols. In the Scandinavian Simvastatin Survival Study (4S), no reduction was observed in recurrence of coronary heart disease with the use of simvastatin in patients with high baseline plant sterol contents and with marked increase of serum plant sterols during the five-year treatment period. Additional treatment with inhibition of sterol absorption (e.g., with plant stanol esters) was suggested for this particular group of patients.
Ezetimibe also reduces plasma concentrations of the non-cholesterol sterols sitosterol and campesterol, suggesting an effect on the absorption of these compounds. The Niemann-Pick C1-like 1 (NPC1L1) transporter is most likely responsible for the transport of cholesterol and plant sterols from the brush border membrane into the intestinal mucosa.
Pregnant and lactating women, young children, and individuals with rare sterol absorption disorders should exercise particular caution. Assertions of treating or curing diseases, such as coronary heart disease, are prohibited under EU health claim regulations, reflecting regulatory acknowledgment that the cardiovascular benefit pathway is mediated through cholesterol reduction, and direct outcome data are limited.
The cholesterol-lowering effect of sitostanol, particularly when delivered as a fatty acid ester in appropriate food matrices, represents one of the better-evidenced dietary supplement interventions in nutrition science. The evidence base rests on multiple decades of controlled human trials, replicated in diverse populations and confirmed by several independent meta-analyses. The effect is consistent, mechanistically well-understood, and endorsed by major regulatory bodies including EFSA. At the standard evidence-based dose of 2 g/day (as sitostanol ester), LDL reductions of 8–10% are reliably achieved, additive to statin therapy. Higher doses (up to approximately 5 g/day) produce progressively greater reductions up to approximately 16–17% in stanols.
Limitations include: (1) the absence of large prospective cardiovascular outcome trials using sitostanol as the primary intervention; (2) significant formulation-dependence, with poorly solubilised free stanol forms showing little or no benefit; (3) documented reductions in plasma carotenoids of uncertain long-term clinical significance; and (4) heterogeneity of response across individuals, partly attributable to genetic variation in sterol absorption transporters (ABCG5/G8) and apolipoprotein E genotype.
Condiciones de salud que sitostanol puede ayudar a apoyar.
Sitostanol-based plant stanol esters reduce LDL cholesterol, which is causally linked to atherosclerotic plaque development in arterial walls. A randomised controlled trial demonstrated that 6 months of stanol ester consumption lowered LDL and non-HDL cholesterol by ~10% and reduced arterial stiffness in small arteries. Calculations using validated risk equations project a ~23% reduction in 10-year coronary artery disease incidence from dietary phytostanol ester use.
Sitostanol (the saturated derivative of beta-sitosterol) inhibits intestinal cholesterol absorption and lowers LDL-C by 8–15% at 2–3 g/day. EFSA endorses a health claim for plant stanols including sitostanol for LDL-C reduction.
Multiple clinical trials and meta-analyses confirm that sitostanol-based plant stanol esters reduce LDL cholesterol by 5–15% in hypercholesterolaemic populations, and this LDL reduction is projected to translate into meaningful reductions in coronary artery disease risk. Efficacy has been demonstrated in subjects with previous myocardial infarction taking statins. Typical doses of 1.5–3 g/day of plant stanols are used in enriched food products.
Clinical trials specifically in metabolic syndrome subjects show that plant stanol esters lower both LDL cholesterol and serum triglycerides, with larger TG reductions than in normolipidaemic populations. Studies document significant decreases in large and medium VLDL particles in these subjects. A phytosterol RCT in 202 metabolic syndrome subjects found a 15.65% greater reduction in the proportion with high triglycerides versus placebo.
Evidence from pooled analyses of randomised controlled trials shows that plant stanols (principally sitostanol) reduce serum triglycerides modestly (~6%) in unselected hypercholesterolaemic subjects, and more substantially (11–28%) in individuals with elevated baseline triglycerides. The mechanism involves reduced hepatic production of large, triglyceride-rich VLDL-1 particles. A network meta-analysis of 131 trials did not find a statistically significant average effect, indicating the response is baseline-dependent.
Sistemas corporales que sitostanol puede ayudar a apoyar.
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