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Efficacy and Safety of Plant Stanols and Sterols in the Management of Blood Cholesterol Levels

      Foods with plant stanol or sterol esters lower serum cholesterol levels. We summarize the deliberations of 32 experts on the efficacy and safety of sterols and stanols. A meta-analysis of 41 trials showed that intake of 2 g/d of stanols or sterols reduced low-density lipoprotein (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%; adding sterols or stanols to statin medication is more effective than doubling the statin dose. A meta-analysis of 10 to 15 trials per vitamin showed that plasma levels of vitamins A and D are not affected by stanols or sterols. Alpha carotene, lycopene, and vitamin E levels remained stable relative to their carrier molecule, LDL. Beta carotene levels declined, but adverse health outcomes were not expected. Sterol-enriched foods increased plasma sterol levels, and workshop participants discussed whether this would increase risk, in view of the marked increase of atherosclerosis in patients with homozygous phytosterol-emia. This risk is believed to be largely hypothetical, and any increase due to the small increase in plasma plant sterols may be more than offset by the decrease in plasma LDL. There are insufficient data to suggest that plant stanols or sterols either prevent or promote colon carcino-genesis. Safety of sterols and stanols is being monitored by follow-up of samples from the general population; however, the power of such studies to pick up infrequent increases in common diseases, if any exist, is limited. A trial with clinical outcomes probably would not answer remaining questions about infrequent adverse effects. Trials with surrogate end points such as intima-media thickness might corroborate the expected efficacy in reducing atherosclerosis. However, present evidence is sufficient to promote use of sterols and stanols for lowering LDL cholesterol levels in persons at increased risk for coronary heart disease.
      ABC (ATP (adenosine triphosphate)-binding cassette), ABCG5 (ABC subfamily G, member 5), CHD (coronary heart disease), LDL (low-density lipoprotein), NCEP (National Cholesterol Education Program)
      Dietary therapy is the cornerstone of strategies to lower serum low-density lipoprotein (LDL) cholesterol levels and reduce the risk for coronary heart disease (CHD). Incorporating foods fortified with plant sterol and stanol esters into the daily diet can substantially enhance the cholesterol-lowering effect of diet, including in patients who are already taking statin drugs. Thus, the recent introduction of stanol-and sterol-enriched foods in many parts of the world
      • Lichtenstein AH
      • Deckelbaum RJ
      AHA Science Advisory: stanol/sterol ester-containing foods and blood cholesterol levels: a statement for healthcare professionals from the Nutrition Committee of the Council on Nutrition, Physical Activity, and Metabolism of the American Heart Association.
      • Jones PJ
      • Raeini-Sarjaz M
      Plant sterols and their derivatives: the current spread of results.
      • Plat J
      • Mensink RP
      Effects of plant sterols and stanols on lipid metabolism and cardiovascular risk.
      is an important development because CHD is the leading cause of morbidity and mortality worldwide. We summarize the deliberations of 32 experts on lipids, nutrition, and heart disease who met in Stresa, Italy, on March 7-9, 2001, under the auspices of the Nutrition Foundation of Italy to discuss the efficacy, safety, and future research required on plant sterols and stanols. (Note that throughout this article, quantities of sterol and stanol esters are expressed as the equivalent weights of free [ie, un-esterified] sterols and stanols.)

      BACKGROUND

      Sterols have cellular functions in plants analogous to those of cholesterol in animals
      • Vahouny GV
      • Kritchevsky D
      Plant and marine sterols and cholesterol metabolism.
      (the structures of 2 major plant sterols and cholesterol are compared in Figure 1
      • Vissers MN
      • Zock PL
      • Meijer GW
      • Katan MB
      Effect of plant sterols from rice bran oil and triterpene alcohols from sheanut oil on serum lipoprotein concentrations in humans.
      ). More than 40 plant sterols (or phytosterols) have been identified, but sitosterol, campesterol, and stigmasterol are the most abundant. Stanols are saturated sterols (they have no double bonds in the sterol ring structure). The major plant stanols are sitostanol and campestanol; they are much less abundant in nature than sterols. Whereas about 50% of cholesterol is absorbed in the intestinal tract, plant stanols and sterols are absorbed much less: absorption is about 10% to 15% for campesterol and campestanol, 4% to 7% for sitosterol,
      • Salen G
      • Shefer S
      • Nguyen L
      • Ness GC
      • Tint GS
      • Shore V
      Sitosterolemia.
      • Heinemann T
      • Axtmann G
      • von Bergmann K
      Comparison of intestinal absorption of cholesterol with different plant sterols in man.
      • Lütjohann D
      • Björkhem I
      • Beil UF
      • von Bergmann K
      Sterol absorption and sterol balance in phytosterolemia evaluated by deuterium-labeled sterols: effect of sitostanol treatment.
      and 1% for sitostanol.
      • Czubayko F
      • Beumers B
      • Lammsfuss S
      • Lütjohann D
      • von Bergmann K
      A simplified micro-method for quantification of fecal excretion of neutral and acidic sterols for outpatient studies in humans.
      Foods enriched with plant stanol or sterol esters lower serum cholesterol levels by reducing intestinal absorption of cholesterol.
      • Lichtenstein AH
      • Deckelbaum RJ
      AHA Science Advisory: stanol/sterol ester-containing foods and blood cholesterol levels: a statement for healthcare professionals from the Nutrition Committee of the Council on Nutrition, Physical Activity, and Metabolism of the American Heart Association.
      • von Bergmann K
      • Prange W
      • Lütjohann D
      Metabolism and mechanism of action of plant sterols.
      • Jones PJ
      • Raeini-Sarjaz M
      • Ntanios FY
      • Vanstone CA
      • Feng JY
      • Parsons WE
      Modulation of plasma lipid levels and cholesterol kinetics by phytosterol versus phytostanol esters.
      • Normen L
      • Dutta P
      • Lia A
      • Andersson H
      Soy sterol esters and beta-sitostanol ester as inhibitors of cholesterol absorption in human small bowel.
      Stanol (and presumably sterol) esters are hydrolyzed in the upper small gut.
      • Miettinen TA
      • Vuoristo M
      • Nissinen M
      • Jarvinen HJ
      • Gylling H
      Serum, biliary, and fecal cholesterol and plant sterols in colectomized patients before and during consumption of stanol ester margarine.
      Free stanols and sterols presumably displace cholesterol from mixed micelles and thereby reduce intestinal cholesterol absorption, but the exact mechanism is unknown. The effects of stanols and sterols probably involve the ATP (adenosine triphosphate)-binding cassette (ABC) subfamily G, member 5 (ABCG5) and ABCG8 transporter proteins. These membrane proteins selectively pump phytosterols from the enterocytes into the intestinal lumen, thus keeping their absorption low.
      • Lee MH
      • Lu K
      • Hazard S
      • et al.
      Identification of a gene, ABCG5, important in the regulation of dietary cholesterol absorption.
      • Berge KE
      • Tian H
      • Graf GA
      • et al.
      Accumulation of dietary cholesterol in sitosterolemia caused by mutations in adjacent ABC transporters.
      Figure thumbnail gr1
      Figure 1Structures of sterols. Cholesterol is the sterol of mammalian cells. β-Sitosterol is the most common sterol in plants; it differs from cholesterol by having an ethyl group attached at C-24. Hydrogenation of the 5,6 double bond of β-sitosterol converts it into sitostanol.
      • Vissers MN
      • Zock PL
      • Meijer GW
      • Katan MB
      Effect of plant sterols from rice bran oil and triterpene alcohols from sheanut oil on serum lipoprotein concentrations in humans.
      Campesterol and campestanol carry a methyl instead of ethyl group at C-24.
      The lowest amount of sterols and stanols tested in human trials is about 700 to 1000 mg/d.
      • Hendriks HF
      • Weststrate JA
      • van Vliet T
      • Meijer GW
      Spreads enriched with three different levels of vegetable oil sterols and the degree of cholesterol lowering in normocholesterolaemic and mildly hypercholesterolaemic subjects.
      • Vanhanen HT
      • Kajander J
      • Lehtovirta H
      • Miettinen TA
      Serum levels, absorption efficiency, faecal elimination and synthesis of cholesterol during increasing doses of dietary sitostanol esters in hypercholesterolaemic subjects.
      • Hallikainen MA
      • Sarkkinen ES
      • Uusitupa MI
      Plant stanol esters affect serum cholesterol concentrations of hypercholesterolemic men and women in a dose-dependent manner.
      Most recent studies used amounts of 1500 to 3300 mg/d of plant stanols or sterols in their esterified, fat-soluble forms. These amounts are much higher than the typical daily intake. In Western populations, the intake of sitosterol is about 150 to 350 mg/d and that of stanols is about 15 to 50 mg/d.
      • Morton GM
      • Lee SM
      • Buss DH
      • Lawrence P
      Intakes and major dietary sources of cholesterol and phytosterols in the British diet.
      • Miettinen TA
      • Tilvis RS
      • Kesaniemi YA
      Serum plant sterols and cholesterol precursors reflect cholesterol absorption and synthesis in volunteers of a randomly selected male population.
      • Normen AL
      • Brants HA
      • Voorrips LE
      • Andersson HA
      • van den Brandt PA
      • Goldbohm RA
      Plant sterol intakes and colorectal cancer risk in the Netherlands Cohort Study on diet and cancer.
      Vegetarians consume about 325 mg/d of sitosterol and about 60 mg/d of campesterol.
      • Vuoristo M
      • Miettinen TA
      Absorption, metabolism, and serum concentrations of cholesterol in vegetarians: effects of cholesterol feeding.
      Thus, the usual daily intake of plant sterols and stanols ranges from 150 to 400 mg/d.
      The cholesterol-lowering effect of extremely high intakes of plant sterols (10-20 g/d) was recognized in the 1950s through the 1970s
      • Jones PJ
      • Raeini-Sarjaz M
      Plant sterols and their derivatives: the current spread of results.
      • Pollak OJ
      • Kritchevsky D
      • Cater NB
      • Grundy SM
      Lowering serum cholesterol with plant sterols and stanols: historical perspectives.
      and reviewed by 2 pioneers in the field.
      • Pollak OJ
      • Kritchevsky D
      Cholesterol balance studies established that this effect was due to reduced cholesterol absorption.
      • Grundy SM
      • Ahrens Jr, EH
      • Davignon J
      The interaction of cholesterol absorption and cholesterol synthesis in man.
      However, widespread use of plant sterols as cholesterol-lowering agents was limited by the bulk and taste of large amounts of these agents and by the introduction of more effective cholesterol-lowering agents. Subsequent studies and demonstration of CHD risk reduction in cholesterol-lowering clinical trials renewed interest in plant sterols. An amount of 3 g/d was as effective as higher amounts in reducing cholesterol absorption if presented in appropriate physical form.
      • Grundy SM
      • Mok HY
      Determination of cholesterol absorption in man by intestinal perfusion.
      Mattson et al
      • Mattson FH
      • Volpenhein RA
      • Erickson BA
      Effect of plant sterol esters on the absorption of dietary cholesterol.
      suggested the esterification process to make plant sterols soluble in dietary fat. Esterifi-cation of sitostanol or sitosterol with fatty acids was found to enhance both their solubility in mayonnaise and margarines and their dispersion in the intestine, thereby promoting their efficacy.
      Margarines containing either plant stanol or sterol esters are marketed in many countries. Other formulations, including yogurt, cream cheese spreads, and cereal bars, have been introduced in some countries, and cereals and fruit juice containing free (ie, unesterified) plant sterols and stanols are being test-marketed in the United States.
      • Jones PJ
      • Raeini-Sarjaz M
      • Ntanios FY
      • Vanstone CA
      • Feng JY
      • Parsons WE
      Modulation of plasma lipid levels and cholesterol kinetics by phytosterol versus phytostanol esters.
      • Jones PJ
      • Ntanios FY
      • Raeini-Sarjaz M
      • Vanstone CA
      Cholesterol-lowering efficacy of a sitostanol-containing phytosterol mixture with a prudent diet in hyperlipidemic men.
      Given the increased marketing of these products, a review of efficacy and safety is timely.

      EFFICACY

       What Is the Effect of Various Sterols and Stanols on Plasma Lipoproteins?

      Data from published randomized trials that tested foods containing stanols or sterols are summarized in Table 1
      • Vissers MN
      • Zock PL
      • Meijer GW
      • Katan MB
      Effect of plant sterols from rice bran oil and triterpene alcohols from sheanut oil on serum lipoprotein concentrations in humans.
      • Jones PJ
      • Raeini-Sarjaz M
      • Ntanios FY
      • Vanstone CA
      • Feng JY
      • Parsons WE
      Modulation of plasma lipid levels and cholesterol kinetics by phytosterol versus phytostanol esters.
      • Hallikainen MA
      • Sarkkinen ES
      • Uusitupa MI
      Plant stanol esters affect serum cholesterol concentrations of hypercholesterolemic men and women in a dose-dependent manner.
      • Jones PJ
      • Ntanios FY
      • Raeini-Sarjaz M
      • Vanstone CA
      Cholesterol-lowering efficacy of a sitostanol-containing phytosterol mixture with a prudent diet in hyperlipidemic men.
      • Williams CL
      • Bollella MC
      • Strobino BA
      • Boccia L
      • Campanaro L
      Plant stanol ester and bran fiber in childhood: effects of lipids, stool weight and stool frequency in preschool children.
      • Tammi A
      • Ronnemaa T
      • Gylling H
      • et al.
      Plant stanol ester margarine lowers serum total and low-density lipoprotein cholesterol concentrations of healthy children: the STRIP Project.
      • Matvienko OA
      • Lewis DS
      • Swanson M
      • et al.
      A single daily dose of soybean phytosterols in ground beef decreases serum total cholesterol and LDL cholesterol in young, mildly hypercholesterolemic men.
      • Plat J
      • van Onselen EN
      • van Heugten MM
      • Mensink RP
      Effects on serum lipids, lipoproteins and fat soluble antioxidant concentrations of consumption frequency of margarines and shortenings enriched with plant stanol esters.
      • Plat J
      • Mensink RP
      Vegetable oil based versus wood based stanol ester mixtures: effects on serum lipids and hemostatic factors in non-hypercholesterolemic subjects.
      • Jones PJ
      • Howell T
      • MacDougall DE
      • Feng JY
      • Parsons W
      Short-term administration of tall oil phytosterols improves plasma lipid profiles in subjects with different cholesterol levels.
      • Mensink RP
      • Ebbing S
      • Lindhout M
      • Plat J
      • van Heugten MM
      Effects of plant stanol esters supplied in a low-fat yoghurt on serum lipids and lipoproteins, non-cholesterol sterols and fat soluble antioxidant concentrations.
      • Niinikoski H
      • Viikari J
      • Palmu T
      Cholesterol-lowering effect and sensory properties of sitostanol ester margarine in normocholesterolemic adults.
      • Mussner MJ
      • Parhofer KG
      • von Bergmann K
      • Schwandt P
      • Broedl U
      • Otto C
      Effects of phytosterol ester-enriched margarine on plasma lipoproteins in mild to moderate hypercholesterolemia are related to basal cholesterol and fat intake.
      • Hallikainen MA
      • Uusitupa MI
      Effects of 2 low-fat stanol ester-containing margarines on serum cholesterol concentrations as part of a low-fat diet in hypercholesterolemic subjects.
      • Sierksma A
      • Weststrate JA
      • Meijer GW
      Spreads enriched with plant sterols, either esterified 4,4-dimethylsterols or free 4-desmethylsterols, and plasma total- and LDL-cholesterol concentrations.
      • Weststrate JA
      • Meijer GW
      Plant sterol-enriched margarines and reduction of plasma total- and LDL-cholesterol concentrations in normocholesterolaemic and mildly hypercholesterolaemic subjects.
      • Miettinen TA
      • Vanhanen H
      Dietary sitostanol related to absorption, synthesis and serum level of cholesterol in different apolipoprotein E phenotypes.
      • Davidson MH
      • Maki KC
      • Umporowics DM
      • et al.
      Safety and tolerability of esterifed phytosterols administered in reduced-fat spread and salad dressing to healthy adult men and women.
      • Vanhanen HT
      • Blomqvist S
      • Ehnholm C
      • et al.
      Serum cholesterol, cholesterol precursors, and plant sterols in hypercholesterolemic subjects with different apoE phenotypes during dietary sitostanol ester treatment.
      • Homma Y
      • Ishikawa T
      • Tateno M
      • Mitaniyama A
      • Sugano M
      Cholesterol and apolipoprotein-lowering effect of plant stanol ester in healthy Japanese men and women.
      • Vanstone CA
      • Raeini-Sarjaz M
      • Parsons WE
      • Jones PJ
      Unesterified plant sterols and stanols lower LDL-cholesterol concentrations equivalently in hypercholesterolemic persons.
      • Hallikainen MA
      • Sarkkinen ES
      • Gylling H
      • Erkkila AT
      • Uusitupa MI
      Comparison of the effects of plant sterol ester and plant stanol ester-enriched margarines in lowering serum cholesterol concentrations in hypercholesterolaemic subjects on a low-fat diet.
      • Miettinen TA
      • Puska P
      • Gylling H
      • Vanhanen HT
      • Vartiainen E
      Reduction of serum cholesterol with sitostanol-ester margarine in a mildly hypercholesterolemic population.
      • Gylling H
      • Puska P
      • Vartiainen E
      • Miettinen TA
      Retinol, vitamin D, carotenes and alpha-tocopherol in serum of a moderately hypercholesterolemic population consuming sitostanol ester margarine.
      • Gylling H
      • Radhakrishnan R
      • Miettinen TA
      Reduction of serum cholesterol in postmenopausal women with previous myocardial infarction and cholesterol malabsorption induced by dietary sitostanol ester margarine: women and dietary sitostanol.
      • Christiansen LI
      • Lähteenmäki PL
      • Mannelin MR
      • Seppänen-Laakso TE
      • Hiltunen RV
      • Yliruusi JK
      Cholesterol-lowering effect of spreads enriched with microcrystalline plant sterols in hypercholesterolemic subjects.
      • Volpe R
      • Niittynen L
      • Korpela R
      • et al.
      Effects of yoghurt enriched with plant sterols on serum lipids in patients with moderate hypercholesterolaemia.
      • Raeini-Sarjaz M
      • Ntanios FY
      • Vanstone CA
      • Jones PJ
      No changes in serum fat-soluble vitamin and carotenoid concentrations with the intake of plant sterol/stanol esters in the context of a controlled diet.
      • Neil HA
      • Meijer GW
      • Roe LS
      Randomised controlled trial of use by hypercholesterolaemic patients of a vegetable oil sterol-enriched fat spread.
      • Gylling H
      • Miettinen TA
      Cholesterol reduction by different plant stanol mixtures and with variable fat intake.
      • Nguyen TT
      • Dale LC
      • von Bergmann K
      • Croghan IT
      Cholesterol-lowering effect of stanol ester in a US population of mildly hypercholesterolemic men and women: a randomized controlled trial.
      • Andersson A
      • Karlström B
      • Mohsen R
      • Vessby B
      Cholesterol-lowering effects of a stanol ester-containing low-fat margarine used in conjunction with a strict lipid-lowering diet.
      • Blair SN
      • Capuzzi DM
      • Gottlieb SO
      • Nguyen T
      • Morgan JM
      • Cater NB
      Incremental reduction of serum total cholesterol and low-density lipoprotein cholesterol with the addition of plant stanol ester-containing spread to statin therapy.
      • Tikkanen MJ
      • Högström P
      • Tuomilehto J
      • Keinänen-Kiukaanniemi S
      • Sundvall J
      • Karppanen H
      Effect of a diet based on low-fat foods enriched with nonesterified plant sterols and mineral nutrients on serum cholesterol.
      • 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.
      • Gylling H
      • Miettinen TA
      Serum cholesterol and cholesterol and lipoprotein metabolism in hypercholesterolaemic NIDDM patients before and during sitostanol ester-margarine treatment.
      • Nigon F
      • Serfaty-Lacrosnière C
      • Beucler I
      • et al.
      Plant sterol-enriched margarine lowers plasma LDL in hyperlipidemic subjects with low cholesterol intake: effect of fibrate treatment.
      • Maki KC
      • Davidson MH
      • Umporowicz DM
      • et al.
      Lipid responses to plant-sterol-enriched reduced-fat spreads incorporated into a National Cholesterol Education Program Step I diet.
      • Nestel P
      • Cehun M
      • Pomeroy S
      • Abbey M
      • Weldon G
      Cholesterol-lowering effects of plant sterol esters and non-esterified stanols in margarine, butter and low-fat foods.
      ; data from these trials updated a previous meta-analysis.
      • Law M
      Plant sterol and stanol margarines and health.
      The trials were identified from MEDLINE and from review articles and by questioning the expert participants at our workshop. In total, 41 trials were identified, with 58 treatment arms or periods and 41 placebo arms or periods. The sterols and stanols were esterified except in 2 trials in which they were directly solubilized in fat-containing foods. The stanols and sterols were added to margarine (or to mayonnaise, olive oil, or butter in 7 trials), and placebo margarines or other foods were used to make the trials double-blind. In each trial, the average placebo-adjusted reduction in LDL cholesterol was calculated. Using STATA statistical software (Stata Corp, College Station, Tex), we determined the average reduction in LDL cholesterol across all the trials and across specified subgroups of trials. A random effects model was used; however, there was no statistically significant heterogeneity between trial results. Therefore, the summary estimates are equivalent to weighting the result of each trial by the inverse of its variance. The subjects in these trials often were selected for having relatively high cholesterol levels, but the effect of such selection proved slight because the average LDL cholesterol levels in the placebo groups were close to the age-specific average values for northern Europe where most of the trials were done (mean LDL values in the placebo groups across all trials were 137 mg/dL or 3.55 mmol/L at ages 45-54 years and 161 mg/dL or 4.17 mmol/L at ages 55-64 years). Trials in children with familial hypercholesterolemia were not included in the analysis and are discussed separately.
      Table 1Randomized Double-Blind Trials Comparing Foods With and Without Added Plant Stanols or Sterols
      * Brackets indicate multiple treatment groups. LDL = low-density lipoprotein; NA = not applicable.
      No. of participants
      Parallel trials
      ReferenceCountryCrossover trialsTreatmentPlaceboMean age (y)Duration (wk)Stanol or sterolDose (g/d)Placebo-adjusted reduction in serum LDL cholesterol (mg/dL)
      Williams et al
      • Williams CL
      • Bollella MC
      • Strobino BA
      • Boccia L
      • Campanaro L
      Plant stanol ester and bran fiber in childhood: effects of lipids, stool weight and stool frequency in preschool children.
      United States19NANA44Stanol1.011
      Tammi
      • Tammi A
      • Ronnemaa T
      • Gylling H
      • et al.
      Plant stanol ester margarine lowers serum total and low-density lipoprotein cholesterol concentrations of healthy children: the STRIP Project.
      Finland72NANA613Stanol1.68
      Vissers et al
      • Vissers MN
      • Zock PL
      • Meijer GW
      • Katan MB
      Effect of plant sterols from rice bran oil and triterpene alcohols from sheanut oil on serum lipoprotein concentrations in humans.
      The Netherlands60NANA233Sterol2.18
      Matvienko et al
      • Matvienko OA
      • Lewis DS
      • Swanson M
      • et al.
      A single daily dose of soybean phytosterols in ground beef decreases serum total cholesterol and LDL cholesterol in young, mildly hypercholesterolemic men.
      United StatesNA1717234Sterol2.717
      Plat et al
      • Plat J
      • van Onselen EN
      • van Heugten MM
      • Mensink RP
      Effects on serum lipids, lipoproteins and fat soluble antioxidant concentrations of consumption frequency of margarines and shortenings enriched with plant stanol esters.
      The Netherlands39NANA314Sterol2.512
      Plat & Mensink
      • Plat J
      • Mensink RP
      Vegetable oil based versus wood based stanol ester mixtures: effects on serum lipids and hemostatic factors in non-hypercholesterolemic subjects.
      The NetherlandsNA7042338Stanol4.014
      Jones et al
      • Jones PJ
      • Howell T
      • MacDougall DE
      • Feng JY
      • Parsons W
      Short-term administration of tall oil phytosterols improves plasma lipid profiles in subjects with different cholesterol levels.
      Canada22NANA351.4Sterol1.612
      Mensink et al
      • Mensink RP
      • Ebbing S
      • Lindhout M
      • Plat J
      • van Heugten MM
      Effects of plant stanol esters supplied in a low-fat yoghurt on serum lipids and lipoproteins, non-cholesterol sterols and fat soluble antioxidant concentrations.
      The NetherlandsNA3030364Stanol3.015
      Hendriks et al
      • Hendriks HF
      • Weststrate JA
      • van Vliet T
      • Meijer GW
      Spreads enriched with three different levels of vegetable oil sterols and the degree of cholesterol lowering in normocholesterolaemic and mildly hypercholesterolaemic subjects.
      The Netherlands80NANA373.5Sterol0.88
      Sterol1.610
      Sterol3.212
      Niinikoski et al
      • Niinikoski H
      • Viikari J
      • Palmu T
      Cholesterol-lowering effect and sensory properties of sitostanol ester margarine in normocholesterolemic adults.
      FinlandNA1212375Stanol3.019
      Mussner et al
      • Mussner MJ
      • Parhofer KG
      • von Bergmann K
      • Schwandt P
      • Broedl U
      • Otto C
      Effects of phytosterol ester-enriched margarine on plasma lipoproteins in mild to moderate hypercholesterolemia are related to basal cholesterol and fat intake.
      Germany63NANA423Sterol1.810
      Hallikainen & Uusitupa
      • Hallikainen MA
      • Uusitupa MI
      Effects of 2 low-fat stanol ester-containing margarines on serum cholesterol concentrations as part of a low-fat diet in hypercholesterolemic subjects.
      FinlandNA3817438Stanol2.318
      Sierksma et al
      • Sierksma A
      • Weststrate JA
      • Meijer GW
      Spreads enriched with plant sterols, either esterified 4,4-dimethylsterols or free 4-desmethylsterols, and plasma total- and LDL-cholesterol concentrations.
      The Netherlands76NANA443Sterol0.77
      Weststrate & Meijer
      • Weststrate JA
      • Meijer GW
      Plant sterol-enriched margarines and reduction of plasma total- and LDL-cholesterol concentrations in normocholesterolaemic and mildly hypercholesterolaemic subjects.
      The Netherlands80NANA453.5Stanol2.716
      Sterol3.217
      Miettinen & Vanhanen
      • Miettinen TA
      • Vanhanen H
      Dietary sitostanol related to absorption, synthesis and serum level of cholesterol in different apolipoprotein E phenotypes.
      FinlandNA[7]8459Sterol0.810
      NA[9]NANANAStanol1.011
      Davidson et al
      • Davidson MH
      • Maki KC
      • Umporowics DM
      • et al.
      Safety and tolerability of esterifed phytosterols administered in reduced-fat spread and salad dressing to healthy adult men and women.
      United StatesNA2121458Sterol3.05
      Vanhanen et al
      • Vanhanen HT
      • Blomqvist S
      • Ehnholm C
      • et al.
      Serum cholesterol, cholesterol precursors, and plant sterols in hypercholesterolemic subjects with different apoE phenotypes during dietary sitostanol ester treatment.
      FinlandNA3433466Stanol3.413
      Vanhanen et al
      • Vanhanen HT
      • Kajander J
      • Lehtovirta H
      • Miettinen TA
      Serum levels, absorption efficiency, faecal elimination and synthesis of cholesterol during increasing doses of dietary sitostanol esters in hypercholesterolaemic subjects.
      FinlandNA[7]8476Stanol0.811
      NA[7]NANANAStanol2.021
      Homma et al
      • Homma Y
      • Ishikawa T
      • Tateno M
      • Mitaniyama A
      • Sugano M
      Cholesterol and apolipoprotein-lowering effect of plant stanol ester in healthy Japanese men and women.
      JapanNA[34]34474Stanol2.013
      NA[36]NANANAStanol3.010
      Vanstone et al
      • Vanstone CA
      • Raeini-Sarjaz M
      • Parsons WE
      • Jones PJ
      Unesterified plant sterols and stanols lower LDL-cholesterol concentrations equivalently in hypercholesterolemic persons.
      Canada15NANA483Sterol1.816
      Stanol1.816
      Hallikainen et al
      • Hallikainen MA
      • Sarkkinen ES
      • Gylling H
      • Erkkila AT
      • Uusitupa MI
      Comparison of the effects of plant sterol ester and plant stanol ester-enriched margarines in lowering serum cholesterol concentrations in hypercholesterolaemic subjects on a low-fat diet.
      Finland34NANA494Sterol2.117
      Stanol2.021
      Miettinen et al
      • Miettinen TA
      • Puska P
      • Gylling H
      • Vanhanen HT
      • Vartiainen E
      Reduction of serum cholesterol with sitostanol-ester margarine in a mildly hypercholesterolemic population.
      FinlandNA[51]515052Stanol1.816
      and Gylling et al
      • Gylling H
      • Puska P
      • Vartiainen E
      • Miettinen TA
      Retinol, vitamin D, carotenes and alpha-tocopherol in serum of a moderately hypercholesterolemic population consuming sitostanol ester margarine.
      NA[51]NANANAStanol2.622
      Jones et al
      • Jones PJ
      • Ntanios FY
      • Raeini-Sarjaz M
      • Vanstone CA
      Cholesterol-lowering efficacy of a sitostanol-containing phytosterol mixture with a prudent diet in hyperlipidemic men.
      CanadaNA1616504Stanol1.725
      Gylling et al
      • Gylling H
      • Radhakrishnan R
      • Miettinen TA
      Reduction of serum cholesterol in postmenopausal women with previous myocardial infarction and cholesterol malabsorption induced by dietary sitostanol ester margarine: women and dietary sitostanol.
      Finland22NANA517Stanol3.020
      Christiansen et al
      • Christiansen LI
      • Lähteenmäki PL
      • Mannelin MR
      • Seppänen-Laakso TE
      • Hiltunen RV
      • Yliruusi JK
      Cholesterol-lowering effect of spreads enriched with microcrystalline plant sterols in hypercholesterolemic subjects.
      FinlandNA[47]445126Sterol1.518
      NA[43]NANANASterol3.019
      Hallikainen et al
      • Hallikainen MA
      • Sarkkinen ES
      • Uusitupa MI
      Plant stanol esters affect serum cholesterol concentrations of hypercholesterolemic men and women in a dose-dependent manner.
      Finland22NANA514Stanol0.83
      Stanol1.610
      Stanol2.318
      Stanol3.020
      Volpe et al
      • Volpe R
      • Niittynen L
      • Korpela R
      • et al.
      Effects of yoghurt enriched with plant sterols on serum lipids in patients with moderate hypercholesterolaemia.
      Italy30NANA514Sterol1.013
      Jones et al
      • Jones PJ
      • Raeini-Sarjaz M
      • Ntanios FY
      • Vanstone CA
      • Feng JY
      • Parsons WE
      Modulation of plasma lipid levels and cholesterol kinetics by phytosterol versus phytostanol esters.
      and
      Canada15NANA523Stanol1.810
      Raeini-Sarjaz et al
      • Raeini-Sarjaz M
      • Ntanios FY
      • Vanstone CA
      • Jones PJ
      No changes in serum fat-soluble vitamin and carotenoid concentrations with the intake of plant sterol/stanol esters in the context of a controlled diet.
      Sterol1.922
      Neil et al
      • Neil HA
      • Meijer GW
      • Roe LS
      Randomised controlled trial of use by hypercholesterolaemic patients of a vegetable oil sterol-enriched fat spread.
      Britain29NANA528Sterol2.520
      Gylling & Miettinen
      • Gylling H
      • Miettinen TA
      Cholesterol reduction by different plant stanol mixtures and with variable fat intake.
      Finland21NANA535Stanol2.417
      Nguyen et al
      • Nguyen TT
      • Dale LC
      • von Bergmann K
      • Croghan IT
      Cholesterol-lowering effect of stanol ester in a US population of mildly hypercholesterolemic men and women: a randomized controlled trial.
      United StatesNA7776538Stanol2.08
      Stanol3.017
      Andersson et al
      • Andersson A
      • Karlström B
      • Mohsen R
      • Vessby B
      Cholesterol-lowering effects of a stanol ester-containing low-fat margarine used in conjunction with a strict lipid-lowering diet.
      SwedenNA1921558Stanol2.011
      Blair et al
      • Blair SN
      • Capuzzi DM
      • Gottlieb SO
      • Nguyen T
      • Morgan JM
      • Cater NB
      Incremental reduction of serum total cholesterol and low-density lipoprotein cholesterol with the addition of plant stanol ester-containing spread to statin therapy.
      United StatesNA7177568Stanol3.015
      Tikkanen et al
      • Tikkanen MJ
      • Högström P
      • Tuomilehto J
      • Keinänen-Kiukaanniemi S
      • Sundvall J
      • Karppanen H
      Effect of a diet based on low-fat foods enriched with nonesterified plant sterols and mineral nutrients on serum cholesterol.
      FinlandNA3635565Sterol0.910
      NA3635565Sterol1.914
      NA3635565Sterol4.215
      Noakes et al
      • 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.
      Australia46NANA573Sterol2.313
      Stanol2.516
      35NANA573Sterol2.015
      Gylling & Miettinen
      • Gylling H
      • Miettinen TA
      Serum cholesterol and cholesterol and lipoprotein metabolism in hypercholesterolaemic NIDDM patients before and during sitostanol ester-margarine treatment.
      Finland11NANA586Stanol3.020
      Nigon et al
      • Nigon F
      • Serfaty-Lacrosnière C
      • Beucler I
      • et al.
      Plant sterol-enriched margarine lowers plasma LDL in hyperlipidemic subjects with low cholesterol intake: effect of fibrate treatment.
      France53NANA588Sterol1.69
      Maki et al
      • Maki KC
      • Davidson MH
      • Umporowicz DM
      • et al.
      Lipid responses to plant-sterol-enriched reduced-fat spreads incorporated into a National Cholesterol Education Program Step I diet.
      United StatesNA[90]39595Sterol1.117
      NA[90]NANANASterol2.220
      Nestel et al
      • Nestel P
      • Cehun M
      • Pomeroy S
      • Abbey M
      • Weldon G
      Cholesterol-lowering effects of plant sterol esters and non-esterified stanols in margarine, butter and low-fat foods.
      Australia15NANA604Sterol2.423
      * Brackets indicate multiple treatment groups. LDL = low-density lipoprotein; NA = not applicable.
      The absolute placebo-adjusted reduction in LDL cholesterol produced by sterols and stanols increases with age (Table 2); this may be due to the increase of the baseline values of LDL cholesterol with age. The percentage reduction in LDL cholesterol did not vary significantly with age.
      Table 2Summary Estimates From Randomized Placebo-Controlled Trials of the Absolute and Percentage Reductions in LDL Cholesterol According to Age
      * Data are from 50 trial arms (in adults) that tested daily doses of stanols/sterols of ≥1.5 g/d. CI = confidence interval; LDL = low-density lipo-protein.
      Reductions in LDL cholesterol
      Mean age of trial subjects (y)No. of trial armsAbsolute (mg/dL) (95% CI)% (95% CI)
      4–628 (7-9)8.0 (5.2-10.8)
      20–29211 (2-19)10.0 (7.0-13.0)
      30–39712 (10-14)10.5 (8.3-12.6)
      40–491315 (13-17)10.3 (8.5-12.0)
      50–602616 (14-18)9.6 (8.4-10.7)
      * Data are from 50 trial arms (in adults) that tested daily doses of stanols/sterols of ≥1.5 g/d. CI = confidence interval; LDL = low-density lipo-protein.
      The percentage reduction in LDL cholesterol as a function of dose is shown in Figure 2 and Table 3. The effect appeared to taper off at intakes of about 2 g/d or more, and there is little additional effect at doses higher than 2.5 g/d (Table 3): The maximum effect is an estimated 11.3%. In the trials, testing doses of 0.7 to 1.1 g/d suggested that approximately half the effect may be attained at this dose. In an analysis that excluded 2 trials in children and 8 low-dose (≤1.1 g/d) trials in adults, the mean reduction in the LDL cholesterol level was 10.1% (95% confidence interval, 8.9%-11.3%) in 27 trials testing stanols (mean dose, 2.5 g/d) and 9.7% (95% confidence interval, 8.5%-10.8%) in 21 trials testing sterols (mean dose, 2.3 g/d). The difference was not significant although the comparison lacked the statistical power to detect a moderate difference. Therefore, these trials cannot support a claim that either is better than the other. Although increases in high-density lipoprotein levels and reductions in triglyceride levels have been seen sporadically,
      • Gylling H
      • Miettinen TA
      Cholesterol reduction by different plant stanol mixtures and with variable fat intake.
      • Gylling H
      • Miettinen TA
      Serum cholesterol and cholesterol and lipoprotein metabolism in hypercholesterolaemic NIDDM patients before and during sitostanol ester-margarine treatment.
      stanols and sterols in general produced little or no change in high-density lipoprotein or very low-density lipoprotein cholesterol, so the absolute reductions in LDL and total cholesterol levels were almost identical. Stanols lower LDL levels by inhibiting LDL apolipoprotein B pro-duction.
      • Gylling H
      • Miettinen TA
      Effects of inhibiting cholesterol absorption and synthesis on cholesterol and lipoprotein metabolism in hypercholesterolemic non-insulin-dependent diabetic men.
      The response curve for apolipoprotein B was similar to that for LDL cholesterol, suggesting that stanols and sterols lower LDL by reducing the number of particles rather than their size or composition.
      • Hallikainen MA
      • Sarkkinen ES
      • Uusitupa MI
      Plant stanol esters affect serum cholesterol concentrations of hypercholesterolemic men and women in a dose-dependent manner.
      • Blomqvist SM
      • Jauhiainen M
      • Van Tol A
      • Hyvönen M
      • Torstila I
      • Vanhanen HT
      Effect of sitostanol ester on composition and size distribution of LDL and HDL.
      Figure thumbnail gr2
      Figure 2Summary estimates from randomized placebo-controlled trials of the percentage reductions in low-density lipopro-tein (LDL) cholesterol with 95% confidence intervals according to dose. The area of each circle is proportional to the total number of persons in the trials in each dose range. The ranges of daily doses shown (number of trial arms in parentheses) are 0.7 to 1.1 g (8), 1.5 to 1.9 g (13), 2.0 to 2.4 g (14), 2.5 to 2.9 g (5), 3.0 to 3.4 g (13), and 4.0 to 4.2 g (2). (Two trials in children were omitted because doses are not equivalent in children and adults.)
      Table 3Mean Percentage Reductions in LDL Cholesterol According to Dose
      * Data are from 56 trial arms that tested stanols/sterols (2 trials in children excluded). CI = confidence interval; LDL = low-density lipoprotein.
      Dose of sterol and stanol (g/d)No. of trial armsReduction in LDL cholesterol (%) (95% CI)
      0.7–1.186.7 (4.9-8.6)
      1.5–1.9138.5 (7.0-10.1)
      2.0–2.4148.9 (7.4-10.5)
      >2.52111.3 (10.2-12.3)
      * Data are from 56 trial arms that tested stanols/sterols (2 trials in children excluded). CI = confidence interval; LDL = low-density lipoprotein.
      The effect of stanols and sterols on plasma lipoproteins is primarily established within a few weeks, and it remained stable in studies lasting 1 year.
      • Miettinen TA
      • Puska P
      • Gylling H
      • Vanhanen HT
      • Vartiainen E
      Reduction of serum cholesterol with sitostanol-ester margarine in a mildly hypercholesterolemic population.
      In these studies, treatment with 1.8 g/d of stanols lowered LDL cholesterol by 8.5% after 1 year,
      • Miettinen TA
      • Puska P
      • Gylling H
      • Vanhanen HT
      • Vartiainen E
      Reduction of serum cholesterol with sitostanol-ester margarine in a mildly hypercholesterolemic population.
      and treatment with 1.6 g/d of sterols lowered LDL cholesterol by 5.9% after 1 year,
      • Hendriks HF
      • Brink EJ
      • Meijer GW
      • Princen HM
      • Ntanios FY
      Safety of long-term consumption of plant sterol esters-enriched spread.
      both relative to the change in the concurrent placebo group. The issue of whether this shows a difference in long-term efficacy between sterols and stanols was debated extensively by the experts, but firm conclusions are impossible because the data are limited to single studies, the doses were somewhat different, and there are no hard data on compliance. More information on these long-term effects obviously is needed.

       What Is the Effect of Formulation?

      The physical form of the sterols and stanols is important. Free (ie, unesterified) sterols and stanols can have the same effect on plasma lipoproteins as stanol and sterol esters
      • Jones PJ
      • Raeini-Sarjaz M
      Plant sterols and their derivatives: the current spread of results.
      • Jones PJ
      • Ntanios FY
      • Raeini-Sarjaz M
      • Vanstone CA
      Cholesterol-lowering efficacy of a sitostanol-containing phytosterol mixture with a prudent diet in hyperlipidemic men.
      ; however, the matrix and emulsification are important, and negative results are common.
      • Denke MA
      Lack of efficacy of low-dose sitostanol therapy as an adjunct to a cholesterol-lowering diet in men with moderate hypercholesterolemia.
      Therefore, new food forms should be evaluated for efficacy if they differ greatly from previously tested forms. One study
      • Ostlund Jr, RE
      • Spilburg CA
      • Stenson WF
      Sitostanol administered in lecithin micelles potently reduces cholesterol absorption in human subjects.
      showed that free stanols emulsified with lecithin reduced cholesterol absorption by 37% in single-meal tests. There is also evidence for efficacy of free plant sterols dissolved in diacylglycerol
      • Meguro S
      • Higashi K
      • Hase T
      • et al.
      Solubilization of phytosterols in diacylglycerol versus triacylglycerol improves the serum cholesterol-lowering effect.
      and of plant sterol and stanol esters incorporated into low-fat products such as bread and cereals
      • Nestel P
      • Cehun M
      • Pomeroy S
      • Abbey M
      • Weldon G
      Cholesterol-lowering effects of plant sterol esters and non-esterified stanols in margarine, butter and low-fat foods.
      or low-fat yogurt.
      The effects of dimethylsterols from rice bran on lipopro-teins are less than those of sterols derived from cholesterol, such as sitosterol (Figure 1).
      • Vissers MN
      • Zock PL
      • Meijer GW
      • Katan MB
      Effect of plant sterols from rice bran oil and triterpene alcohols from sheanut oil on serum lipoprotein concentrations in humans.

       What Are the Effects of Intake Frequency?

      In most of the trials, the total daily intake of plant stanols and sterols was divided into 2 or 3 portions over the day, but 1 study showed that 2.5 g of plant stanols taken at lunch produced the same LDL-lowering effects as 2.5 g of plant stanols divided over the 3 meals.
      • Plat J
      • van Onselen EN
      • van Heugten MM
      • Mensink RP
      Effects on serum lipids, lipoproteins and fat soluble antioxidant concentrations of consumption frequency of margarines and shortenings enriched with plant stanol esters.
      Thus, the distribution of intake over the day may not be an important determinant of efficacy, and mechanisms other than replacing cholesterol from mixed micelles for inhibition of cholesterol absorption must be considered because this would presumably require ingestion of stanols and sterols with every meal. More trials to compare the efficacy and effectiveness of different dosing regimens are required. Studies of the effects of sterols and stanols on transporters of cholesterol may also shed light on this issue.
      • Lee MH
      • Lu K
      • Hazard S
      • et al.
      Identification of a gene, ABCG5, important in the regulation of dietary cholesterol absorption.
      • Berge KE
      • Tian H
      • Graf GA
      • et al.
      Accumulation of dietary cholesterol in sitosterolemia caused by mutations in adjacent ABC transporters.

       What Are the Responses of Subgroups Including Children, Patients With Diabetes, and People With Defined Genotypes?

      Two studies showed an LDL cholesterol reduction of about 15% in children with familial hypercholesterolemia treated with stanol esters, which compares favorably with the 8% reduction in children with average levels of LDL cholesterol (Table 2). A study with unesterified sitostanol showed an even more pronounced effect.
      • Becker M
      • Staab D
      • Von Bergmann K
      Treatment of severe familial hypercholesterolemia in childhood with sitosterol and sitostanol.
      Sterol esters also produced a reduction in LDL cholesterol.
      • Neil HA
      • Meijer GW
      • Roe LS
      Randomised controlled trial of use by hypercholesterolaemic patients of a vegetable oil sterol-enriched fat spread.
      Therefore, sterols and stanols appear at least as effective in children with familial hypercholesterolemia as in children not so affected.
      Stanol esters lowered LDL cholesterol levels by 9% in diabetic persons, similar to reductions in nondiabetic per-sons.
      • Gylling H
      • Miettinen TA
      Serum cholesterol and cholesterol and lipoprotein metabolism in hypercholesterolaemic NIDDM patients before and during sitostanol ester-margarine treatment.
      Absorption of cholesterol may be affected by apolipoprotein E genotype, but in most studies, the apolipoprotein E genotype has little effect on the response of LDL to sterols and stanols.
      • Hallikainen MA
      • Sarkkinen ES
      • Uusitupa MI
      Plant stanol esters affect serum cholesterol concentrations of hypercholesterolemic men and women in a dose-dependent manner.
      • Plat J
      • Mensink RP
      Vegetable oil based versus wood based stanol ester mixtures: effects on serum lipids and hemostatic factors in non-hypercholesterolemic subjects.
      • Hallikainen MA
      • Sarkkinen ES
      • Gylling H
      • Erkkila AT
      • Uusitupa MI
      Comparison of the effects of plant sterol ester and plant stanol ester-enriched margarines in lowering serum cholesterol concentrations in hypercholesterolaemic subjects on a low-fat diet.
      • Geelen A
      • Zock PL
      • de Vries JH
      • Katan MB
      Apolipoprotein E polymorphism and serum lipid response to plant sterols in humans.
      Other polymorphisms have not been studied widely.

       Are the Effects of Stanols and Sterols Additive to Those of Diet?

      The effects of stanols and sterols appear to be independent of the background diet.
      • Maki KC
      • Davidson MH
      • Umporowicz DM
      • et al.
      Lipid responses to plant-sterol-enriched reduced-fat spreads incorporated into a National Cholesterol Education Program Step I diet.
      Thus, addition of 2.3 g/d of stanol esters doubled the effect of a low-fat National Cholesterol Education Program (NCEP) step 1 diet, producing a total decrease in the LDL cholesterol level of 23%.
      • Hallikainen MA
      • Uusitupa MI
      Effects of 2 low-fat stanol ester-containing margarines on serum cholesterol concentrations as part of a low-fat diet in hypercholesterolemic subjects.
      Similar effects were seen with free sterols and stanols.
      • Jones PJ
      • Ntanios FY
      • Raeini-Sarjaz M
      • Vanstone CA
      Cholesterol-lowering efficacy of a sitostanol-containing phytosterol mixture with a prudent diet in hyperlipidemic men.
      Therefore, a few participants pointed out that sterols and stanols will lower cholesterol levels even in people eating otherwise unhealthy diets. However, diets recommended for the prevention of CHD provide more than just LDL lowering; they provide dietary fiber, essential fatty acids, vitamins, minerals, and beneficial substances from fruits and vegetables.
      • Jenkins DJ
      • Kendall CW
      • Popovich DG
      • et al.
      Effect of a very-high-fiber vegetable, fruit, and nut diet on serum lipids and colonic function.
      Therefore, most workshop participants believe that sterols and stanols should complement a healthy diet low in saturated fat and cholesterol and high in fruits, vegetables, and whole grains, with unhardened oils as the fat source.

       Are the Effects of Sterols and Stanols Additive to Those of Cholesterol-Lowering Drugs?

      In a trial of 167 adults receiving statin therapy, addition of stanol ester margarine lowered LDL cholesterol levels 10% more than addition of placebo.
      • Blair SN
      • Capuzzi DM
      • Gottlieb SO
      • Nguyen T
      • Morgan JM
      • Cater NB
      Incremental reduction of serum total cholesterol and low-density lipoprotein cholesterol with the addition of plant stanol ester-containing spread to statin therapy.
      Smaller studies in patients with CHD
      • Gylling H
      • Radhakrishnan R
      • Miettinen TA
      Reduction of serum cholesterol in postmenopausal women with previous myocardial infarction and cholesterol malabsorption induced by dietary sitostanol ester margarine: women and dietary sitostanol.
      and in adults with familial hypercho-lesterolemia treated with simvastatin
      • Vuorio AF
      • Gylling H
      • Turtola H
      • Kontula K
      • Ketonen P
      • Miettinen TA
      Stanol ester margarine alone and with simvastatin lowers serum cholesterol in families with familial hypercholesterolemia caused by the FH-North Karelia mutation.
      found additional LDL cholesterol level reductions of 16% and 20%, respectively. In a small study of patients with type 2 diabetes, addition of stanol esters to pravastatin therapy resulted in an LDL cholesterol reduction of 14%.
      • Gylling H
      • Miettinen TA
      Effects of inhibiting cholesterol absorption and synthesis on cholesterol and lipoprotein metabolism in hypercholesterolemic non-insulin-dependent diabetic men.
      Sterols also reduced LDL levels in patients treated with statins.
      • Neil HA
      • Meijer GW
      • Roe LS
      Randomised controlled trial of use by hypercholesterolaemic patients of a vegetable oil sterol-enriched fat spread.
      Adding stanols and sterols appears somewhat more effective than doubling the statin dose, which usually produces an additional lowering of LDL cholesterol levels of only 5% to 7%.
      • Blair SN
      • Capuzzi DM
      • Gottlieb SO
      • Nguyen T
      • Morgan JM
      • Cater NB
      Incremental reduction of serum total cholesterol and low-density lipoprotein cholesterol with the addition of plant stanol ester-containing spread to statin therapy.
      • Bradford RH
      • Shear CL
      • Chremos AN
      • et al.
      Expanded Clinical Evaluation of Lovastatin (EXCEL) study results, I: efficacy in modifying plasma lipoproteins and adverse event profile in 8245 patients with moderate hypercholesterolemia.
      • Jones P
      • Kafonek S
      • Laurora I
      • Hunninghake D
      Comparative dose efficacy study of atorvastatin versus simvastatin, pravastatin, lovastatin, and fluvastatin in patients with hypercholesterolemia (the CURVES study) [published correction appears in Am J Cardiol. 1998;82:128].
      Thus, for patients who are taking statins and need additional cholesterol lowering, it is more effective to add stanols and sterols to their diets than to increase their statin doses, and this option needs to be considered by physicians treating patients with hypercholesterolemia.
      In patients with diabetes in whom cholesterol absorption was inhibited with neomycin, addition of stanol esters lowered LDL levels by 11%.
      • Gylling H
      • Miettinen TA
      The effect of cholesterol absorption inhibition on low density lipoprotein cholesterol level.
      Cholestyramine also seems to produce an additive effect,
      • Gylling H
      • Miettinen TA
      LDL cholesterol lowering by bile acid malabsorption during inhibited synthesis and absorption of cholesterol in hypercholesterolemic coronary subjects.
      but more data are needed, as are data on the combined effects of sterols and stanols with niacin and ezetimibe.

       What Are the Effects on Atherosclerosis in Animals?

      Sterols and stanols lowered arterial lipid accumulation in mice, rabbits, and hamsters
      • Moghadasian MH
      • McManus BM
      • Pritchard PH
      • Frohlich JJ
      “Tall oil”-derived phytosterols reduce atherosclerosis in ApoE-deficient mice.
      • Ntanios FY
      • Jones PJ
      • Frohlich JJ
      Dietary sitostanol reduces plaque formation but not lecithin cholesterol acyl transferase activity in rabbits.
      • Volger OL
      • Mensink RP
      • Plat J
      • Hornstra G
      • Havekes LM
      • Princen HM
      Dietary vegetable oil and wood derived plant stanol esters reduce atherosclerotic lesion size and severity in apoE*3-Leiden transgenic mice.
      • Moghadasian MH
      • McManus BM
      • Godin DV
      • Rodrigues B
      • Frohlich JJ
      Proatherogenic and antiatherogenic effects of probucol and phytosterols in apolipoprotein E-deficient mice: possible mechanisms of action.
      but did not cause regression of established atherosclerosis.
      • Moghadasian MH
      • Godin DV
      • McManus BM
      • Frohlich JJ
      Lack of regression of atherosclerotic lesions in phytosterol-treated apo E-deficient mice.
      In rabbits fed athero-genic diets, plant stanol consumption inhibited development of arterial plaque despite markedly elevated serum cholesterol levels, suggesting a process other than simple lowering of lipid levels.
      • Ntanios FY
      • Jones PJ
      • Frohlich JJ
      Dietary sitostanol reduces plaque formation but not lecithin cholesterol acyl transferase activity in rabbits.

       What Is the Potential Impact for CHD Risk Reduction?

      Data from drug trials
      • Shepherd J
      • Cobbe SM
      • Ford I
      • West of Scotland Coronary Prevention Study Group
      • et al.
      Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia.
      • Downs JR
      • Clearfield M
      • Weis S
      • et al.
      Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS: Air Force/Texas Coronary Atherosclerosis Prevention Study.
      indicate that the reduction in LDL cholesterol levels of about 10% could be expected to reduce the incidence of ischemic heart disease by about 12% to 20% over 5 years. An analysis of cohort studies indicates that the longer-term risk reduction would be about 20%.
      • Law MR
      • Wald NJ
      • Thompson SG
      By how much and how quickly does reduction in serum cholesterol concentration lower risk of ischaemic heart disease?.
      No trials have directly tested the effects of sterols and stanols on CHD incidence; thus, there is a theoretical possibility that the expected beneficial effect on CHD will not be realized fully. However, most workshop participants believe that LDL cholesterol–lowering intervention rarely has failed to reduce the incidence of is-chemic heart disease when tested in randomized trials.
      • Law MR
      • Wald NJ
      • Thompson SG
      By how much and how quickly does reduction in serum cholesterol concentration lower risk of ischaemic heart disease?.
      Other participants would like the reassurance provided by a trial with hard end points.

       How Should Plant Sterols and Stanols Be Incorporated Into the Clinical and Public Health Approaches to Cholesterol Lowering?

      The lowering effect of stanols and sterols on LDL levels of 10% is similar to that of replacing 8% of energy as saturated fat by monounsaturated and polyunsaturated fats.
      • Mensink RP
      • Katan MB
      Effect of dietary fatty acids on serum lipids and lipoproteins: a meta-analysis of 27 trials.
      When sterols and stanols are combined with diets low in saturated fat and cholesterol, reductions of 20% or more can be achieved. The potential utility of plant stanols and sterols in clinical therapeutic lifestyle changes to lower LDL cholesterol levels has been recognized recently by the NCEP.
      • Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III)
      Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP).
      The NCEP's Therapeutic Lifestyle Changes diet thus recommends reduced intakes of saturated fat (<7% of total calories) and cholesterol (<200 mg/d) and encourages use of plant stanols/sterols (2 g/d) and soluble fiber (10-25 g/d) to enhance the LDL cholesterol– lowering effect of diet. Additional LDL lowering can result from weight reduction and increased physical activity, the other components of the Therapeutic Lifestyle Changes.
      The optimal dose of sterol/stanol from margarines is consumed with 7 g of fat, of which 2 g is saturated; low-fat food forms also are available. Therefore, use of stanol-and sterol-containing foods is not expected to have adverse effects on weight or other risk factors. On the basis of current average LDL cholesterol levels in the United States and the recommended LDL cholesterol treatment goals, approximately 65 million US adults are candidates for these lifestyle changes. Also, the therapeutic diet should be an integral part of patient management, even when drug therapy is used, because patients treated with cholesterol-lowering drugs obtain additional significant LDL cholesterol reduction when plant stanols/sterols are added to their diets, enabling many of those not at their LDL goals to achieve those goals. Moreover, concomitant use of plant stanols/sterols may allow lower doses of drugs.
      Plant stanols/sterols can have a role in the clinical management of high LDL cholesterol levels in children, particularly in those with familial hypercholesterolemia. They can facilitate use of lower doses of drugs or delay initiation of drug therapy. Long-term data on use of plant stanols and sterols in children are lacking, and such data are needed. However, data from studies in adults do not suggest any specific concerns regarding use by children. Specifically, levels of vitamin A (retinol) and D, which are particularly important for children, are not affected by the use of sterols and stanols in adults.

      SAFETY

      The safety of stanols and sterols has been reviewed by several regulatory agencies. The US Food and Drug Administration has accepted that plant sterol/stanol esters are asserted to be Generally Recognized as Safe (GRAS) by manufacturers. The Food and Drug Administration also has authorized a claim that foods containing plant sterol/stanol esters may reduce the risk of CHD (Federal Register of September 8, 2000 [65 FR 54686]). The Scientific Committee on Foods of the European Union concluded that phytosterol ester margarine was safe for human use (http://europa.eu.int/comm/food/fs/sc/scf/out56_en.pdf). In-use data of stanol and sterol esters are now available for up to 2 years in the United States and Europe and over 5 years in Finland, and no adverse effects have been reported. Thus, the balance of risk and benefit appears to be favorable. However, the lack of long-term (≥5 years) experience leaves a possibility of unforeseen effects.

       What Do Toxicologic Tests in Animals Say About the Safety of Plant Stanols and Sterols?

      Studies in rats confirm that stanols and sterols are absorbed poorly.
      • Sanders DJ
      • Minter HJ
      • Howes D
      • Hepburn PA
      The safety evaluation of phytosterol esters, part 6: the comparative absorption and tissue distribution of phytosterols in the rat.
      Plant stanols and sterols mainly were detected in the adrenal glands and ovaries. In humans, β-sitosterol can be metabolized to pregnenelone in adrenal glands, testes, and term placentas following the same pathways as cholesterol.
      • Aringer L
      • Eneroth P
      • Nordstrom L
      Side-chain cleavage of 4-cholesten-3-one, 5-cholesten-3 alpha-ol, beta-sitosterol, and related steroids in endocrine tissues from rat and man.
      Whether plant stanols are metabolized in the same way is unknown.
      In 2 studies, high doses of plant sterol esters and stanol esters were fed to rats.
      • Hepburn PA
      • Horner SA
      • Smith M
      Safety evaluation of phytosterol esters, part 2: subchronic 90-day oral toxicity study on phytosterol esters—a novel functional food.
      • Turnbull D
      • Whittaker MH
      • Frankos VH
      • Jonker D
      13-Week oral toxicity study with stanol esters in rats.
      There were no signs of toxicity or adverse effects except for some reduction of fat-soluble vitamins at the highest dose of 5%, equivalent to 4.1 g of plant stanols per kilogram of body weight per day (about 150 times higher than the recommended dose of 2 g/d in humans). In multigenerational rat studies,
      • Waalkens-Berendsen DH
      • Wolterbeek AP
      • Wijnands MV
      • Richold M
      • Hepburn PA
      Safety evaluation of phytosterol esters, part 3: two-generation reproduction study in rats with phytosterol esters—a novel functional food.
      • Whittaker MH
      • Frankos VH
      • Wolterbeek AP
      • Waalkens-Berendsen DH
      Two-generation reproductive toxicity study of plant stanol esters in rats.
      plant sterol esters produced no effects on reproduction or development at up to 5% wt/wt of feed. For plant stanol esters, the No Observed Adverse Effect Level was the mid dose of 2.5% plant stanol because there were treatment-related effects on body weight of offspring in the highdose group.
      There is no evidence of a teratogenic effect for plant sterols and stanols.
      • Slesinski RS
      • Turnbull D
      • Frankos VH
      • Wolterbeek AP
      • Waalkens-Berendsen DH
      Developmental toxicity study of vegetable oil-derived stanol fatty acid esters.
      Some reports say plant sterols and stanols have estrogenic effects
      • Malini T
      • Vanithakumari G
      Effect of beta-sitosterol on uterine biochemistry: a comparative study with estradiol and progesterone.
      • Mellanen P
      • Petanen T
      • Lehtimaki J
      • et al.
      Wood-derived estrogens: studies in vitro with breast cancer cell lines and in vivo in trout.
      • MacLatchy DL
      • Van Der Kraak GJ
      The phytoestrogen beta-sitosterol alters the reproductive endocrine status of goldfish.
      ; however, plant sterols do not bind to the estrogen receptor,
      • Baker VA
      • Hepburn PA
      • Kennedy SJ
      • et al.
      Safety evaluation of phytosterol esters, part 1: assessment of oestrogenicity using a combination of in vivo and in vitro assays.
      and in various in vitro and in vivo assays there is no evidence of estrogenic activity for stanols.
      • Turnbull D
      • Frankos VH
      • Leeman WR
      • Jonker D
      Short-term tests of estrogenic potential of plant stanols and plant stanol esters.
      Plant sterols and stanols are not genotoxic in vitro (bacterial mutation assay; metaphase chromosome analysis of human lymphocytes; mammalian cell gene mutation assay; mammalian cell chromosome aberration assay) or in rats in vivo (unscheduled DNA synthesis in rat liver; induction of micronuclei in rat bone marrow).
      • Turnbull D
      • Whittaker MH
      • Frankos VH
      • Jonker D
      13-Week oral toxicity study with stanol esters in rats.
      • Hepburn PA
      • Lea L
      • Wolfreys A
      The assessment of phytosterols and phytosterol-esters for potential mutagenic activity.
      • Wolfreys AM
      • Hepburn PA
      Safety evaluation of phytosterol esters, part 7: assessment of mutagenic activity of phytosterols, phytosterol esters and the cholesterol derivative, 4-cholesten-3-one.
      Increased consumption of plant stanols and sterols elevated the amount of cholesterol in the large intestine. Cholesterol is metabolized by intestinal microflora into 4-cholesten-3-one, and a small increase in the fecal concentration of 4-cholesten-3-one was found after healthy volunteers consumed 8.6 g/d of phytosterols for 4 weeks.
      • Weststrate JA
      • Ayesh R
      • Bauer-Plank C
      • Drewitt PN
      Safety evaluation of phytosterol esters, part 4: faecal concentrations of bile acids and neutral sterols in healthy normolipidaemic volunteers consuming a controlled diet either with or without a phytosterol ester-enriched margarine.
      4-Cholesten-3-one has been reported to be mutagenic in some tests in vitro.
      • Suzuki K
      • Bruce WR
      • Baptista J
      • Furrer R
      • Vaughan DJ
      • Krepinsky JJ
      Characterization of cytotoxic steroids in human faeces and their putative role in the etiology of human colonic cancer.
      • Kaul HK
      • Couch DB
      • Gingerich JD
      • Bruce WR
      • Heddle JA
      Genotoxicity of two fecal steroids in murine colonic epithelium assessed by the sister chromatid exchange technique.
      However, assessment of 4-cholesten-3-one in a bacterial mutation assay and in an in vitro chromosome aberration assay produced no evidence of mutagenic activity.
      • Wolfreys AM
      • Hepburn PA
      Safety evaluation of phytosterol esters, part 7: assessment of mutagenic activity of phytosterols, phytosterol esters and the cholesterol derivative, 4-cholesten-3-one.
      • Wolfreys A
      • Lea L
      • Hepburn PA
      The assessment of the cholesterol breakdown product 4-cholesten-3-one for potential mutagenic activity.
      One limitation of the animal studies is that the microflora of humans and rats are different. This might affect how plant sterols and stanols and cholesterol are metabolized in the gut. Also, the gastrointestinal systems of the rat and human are distinctly different. Finally, toxicologic studies have been confined to native stanols and sterols. If stanol-and sterol-enriched products were to be marketed for frying purposes, the stability of stanols and sterols on frying would need to be established first.

       How Do Sterols and Stanols Affect the Absorption and Plasma Levels of Phytosterols and Stanols?

      In normal subjects, intake of 2 g/d of plant sterols approximately doubles plasma campesterol levels; sitosterol levels increase also. Increased intake of stanols increases their plasma levels, but stanol concentrations are always a factor of 10 to 100 lower than sterols
      • Hallikainen MA
      • Sarkkinen ES
      • Gylling H
      • Erkkila AT
      • Uusitupa MI
      Comparison of the effects of plant sterol ester and plant stanol ester-enriched margarines in lowering serum cholesterol concentrations in hypercholesterolaemic subjects on a low-fat diet.
      • Nguyen TT
      • Dale LC
      • von Bergmann K
      • Croghan IT
      Cholesterol-lowering effect of stanol ester in a US population of mildly hypercholesterolemic men and women: a randomized controlled trial.
      ; in addition, stanol consumption reduces plasma sterol concentrations.
      • Lütjohann D
      • Björkhem I
      • Beil UF
      • von Bergmann K
      Sterol absorption and sterol balance in phytosterolemia evaluated by deuterium-labeled sterols: effect of sitostanol treatment.
      • Jones PJ
      • Raeini-Sarjaz M
      • Ntanios FY
      • Vanstone CA
      • Feng JY
      • Parsons WE
      Modulation of plasma lipid levels and cholesterol kinetics by phytosterol versus phytostanol esters.
      • Hallikainen MA
      • Sarkkinen ES
      • Gylling H
      • Erkkila AT
      • Uusitupa MI
      Comparison of the effects of plant sterol ester and plant stanol ester-enriched margarines in lowering serum cholesterol concentrations in hypercholesterolaemic subjects on a low-fat diet.
      • Gylling H
      • Puska P
      • Vartiainen E
      • Miettinen TA
      Serum sterols during stanol ester feeding in a mildly hypercholesterolemic population.
      Concentrations of plant sterols in plasma in subjects consuming sterol ester margarine are within the range of 0.6 to 2.0 mg/dL.
      • Weststrate JA
      • Meijer GW
      Plant sterol-enriched margarines and reduction of plasma total- and LDL-cholesterol concentrations in normocholesterolaemic and mildly hypercholesterolaemic subjects.
      • Hallikainen MA
      • Sarkkinen ES
      • Gylling H
      • Erkkila AT
      • Uusitupa MI
      Comparison of the effects of plant sterol ester and plant stanol ester-enriched margarines in lowering serum cholesterol concentrations in hypercholesterolaemic subjects on a low-fat diet.
      This is 20 to 100 times lower than in patients homozygous for phytosterolemia.
      Phytosterolemia (also known as sitosterolemia) is an extremely rare recessive disease.
      • Salen G
      • Shefer S
      • Nguyen L
      • Ness GC
      • Tint GS
      • Shore V
      Sitosterolemia.
      • Björkhem I
      • Boberg KM
      Inborn errors in bile acid biosynthesis and storage of sterols other than cholesterol.
      The homozygous state occurs in about 1 in 5 million people, with a wide margin of uncertainty. Patients are prone to premature atherosclerosis and CHD. Sitosterol absorption in homozygous individuals is typically 15% to 25% as opposed to 5% or less in normal persons, and excretion is reduced. Typical ranges for plasma concentrations are 14 to 65 mg/dL for sitosterol and 7 to 21 mg/dL for campesterol. Mutations in intestinal ABCG5 and ABCG8 transporters are responsible for at least some forms of phytosterolemia.
      • Lee MH
      • Lu K
      • Hazard S
      • et al.
      Identification of a gene, ABCG5, important in the regulation of dietary cholesterol absorption.
      • Berge KE
      • Tian H
      • Graf GA
      • et al.
      Accumulation of dietary cholesterol in sitosterolemia caused by mutations in adjacent ABC transporters.
      • Lu K
      • Lee MH
      • Hazard S
      • et al.
      Two genes that map to the STSL locus cause sitosterolemia: genomic structure and spectrum of mutations involving sterolin-1 and sterolin-2, encoded by ABCG5 and ABCG8, respectively.
      In heterozygous persons (about 1 in 1100), absorption of phytosterols may be normal
      • Lütjohann D
      • Björkhem I
      • Ose L
      Phytosterolaemia in a Norwegian family: diagnosis and characterization of the first Scandinavian case.
      or up to 15%,
      • Salen G
      • Shefer S
      • Nguyen L
      • Ness GC
      • Tint GS
      • Shore V
      Sitosterolemia.
      but body pools are not greatly elevated because removal by the liver is rapid. Plasma levels of plant sterols in heterozygous people are normal or slightly elevated.
      • Lütjohann D
      • von Bergmann K
      Phytosterolaemia: diagnosis, characterization and therapeutical approaches.
      One study showed that consuming sterol margarine increased plasma campes-terol concentrations 2-to 3-fold in people heterozygous for phytosterolemia, which is similar to the effect in people without the mutation.
      • Stalenhoef AF
      • Hectors M
      • Demacker PN
      Effect of plant sterol-enriched margarine on plasma lipids and sterols in subjects heterozygous for phytosterolaemia.
      This is reassuring because het-erozygosity is much more common than homozygosity, and heterozygosity usually is undetected.

       Does Absorption of Plant Sterols and Stanols Promote Atherosclerosis?

      Sterols and stanols have been found in atheroma lesions. Mild hyperphytosterolemia is inherited
      • Berge KE
      • von Bergmann K
      • Lütjohann D
      • et al.
      Heritability of plasma noncholesterol sterols and relationship to DNA sequence polymorphism in ABCG5 and ABCG8.
      and is associated with an augmented risk of premature CHD
      • Glueck CJ
      • Speirs J
      • Tracy T
      • Streicher P
      • Illig E
      • Vandegrift J
      Relationships of serum plant sterols (phytosterols) and cholesterol in 595 hypercholesterolemic subjects, and familial aggregation ofphytosterols, cholesterol, and premature coronary heart disease in hyperphytosterolemic probands and their first-degree relatives.
      • Sudhop T
      • Gottwald BM
      • von Bergmann K
      Serum plant sterols as a potential risk factor for coronary heart disease.
      • Plat J
      • Mensink RP
      Effects of diets enriched with two different plant stanol ester mixtures on plasma ubiquinol-10 and fat-soluble antioxidant concentrations.
      ; it has been suggested that premature atherosclerosis in patients with homozygous phytosterolemia is due to an atherogenic effect of circulating sitosterol and campesterol. However, the high rate of atherosclerosis in patients with phytosterolemia could be due to other consequences of the genetic defect.
      Some workshop participants believe that the slight increase in plasma sterols on consumption of foods enriched with plant sterol esters might detract from the beneficial effect on atherosclerosis produced by the decrease in LDL cholesterol. Others believe that the effect, if any, is completely compensated for by the decrease in plasma LDL. Further studies on the mechanism through which defects in ABC transporters produce atherosclerosis and CHD in patients with phytosterolemia might clarify this point. However, current data, although preliminary, suggest that not only normal subjects but also subjects heterozygous for phytosterolemia can consume plant sterols without adverse effects.
      • Stalenhoef AF
      • Hectors M
      • Demacker PN
      Effect of plant sterol-enriched margarine on plasma lipids and sterols in subjects heterozygous for phytosterolaemia.

       How Do Stanols and Sterols Affect Plasma Levels of Fat-Soluble Vitamins?

      Of the trials of sterols and stanols identified in the meta-analysis on efficacy (Table 1), 18 trials testing doses of 1.5 g/d or more reported plasma concentrations of fat-soluble vitamins. Table 4 summarizes the mean changes across trials. Statistically significant reductions occurred in the plasma concentrations of the hydrocarbon carotenes: alpha carotene by 9%, beta carotene by 28%, and lycopene by 7%. Part of this reduction probably is due to reduced absorption of carotenes and the rest to reduced concentrations of the lipoprotein carrier, LDL; after the decrease in total cholesterol induced by stanols and sterols was corrected for, a statistically significant reduction remained for beta carotene but not for alpha carotene or lycopene. The reduction in α-tocopherol was explained similarly by the reduction in cholesterol (Table 4). The decrease in beta carotene could be prevented by adding sufficient fruits and vegetables to the diet.
      • 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.
      Vitamin D and vitamin A (retinol) concentrations are on average unaffected by sterols and stanols (Table 4). Vitamin K–dependent clotting factors did not change in subjects fed stanols.
      • Plat J
      • Mensink RP
      Vegetable oil based versus wood based stanol ester mixtures: effects on serum lipids and hemostatic factors in non-hypercholesterolemic subjects.
      When 8 patients taking coumarin were given stanol esters, no significant changes occurred in prothrombin time, and no major changes were needed in coumarin dose, suggesting that vitamin K status was unchanged.
      • Nguyen TT
      • Dale LC
      Plant stanol esters and vitamin K [letter].
      Table 4Mean Change (95% CI) in Serum Concentrations of Vitamins in Randomized Placebo-Controlled Trials of Stanols/Sterols
      * Only trials testing doses ≥1.5 g/d are included. CI = confidence interval; NA = not applicable; NS = not significant.
      VitaminNo. of trialsMean change (%)Mean change, adjusted for change in total serum cholesterol (%)References
      α-Tocopherol15–5.9 (−8.0 to −3.8) (P<.001)2.1 (−0.3 to +4.5) (P=NS)16,18,32,35,38,42,46,48,50,52,54,56,59,62,116
      Alpha carotene13–8.7 (−13.8 to −3.5) (P<.001)–0.3 (−5.7 to +5.2) (P=NS)18,32,35,42,46,48,50,52,54,56,59,62,116
      Beta carotene15–19.9 (−24.9 to −15.0) (P<.001)–12.1 (−17.4 to −6.8) (P<.001)18,32,35,38,42,46,48,50,52,54-56,59,62,116
      Lycopene13–7.3 (−13.1 to −1.4) (P=.01)–0.1 (−6.1 to +5.9) (P=NS)16,18,32,35,39,40,42,46,52,56,59,62,116
      Retinol14–0.1 (−1.6 to +1.5)NA18,32,38,42,46,48,50,52,54-56,59,62,116
      Vitamin D10+0.5 (−2.6 to +3.6)NA16,38,42,46,48,52,54-56,62
      * Only trials testing doses ≥1.5 g/d are included. CI = confidence interval; NA = not applicable; NS = not significant.

       Do Reduced Absorption and/or Decreased Plasma Levels of Carotenes Constitute a Health Risk?

      Substances that can reduce circulating carotenoids pose a theoretical public health concern because low levels of circulating carotenoids have been associated with increased risk of several chronic diseases including CHD, certain cancers, and macular degeneration.
      • Kritchevsky SB
      Beta-carotene, carotenoids and the prevention of coronary heart disease.
      • Expert Panel of the Diet and Cancer Project
      • Institute of Medicine
      • Food and Nutrition Board
      In observational studies, lutein has been inversely associated with macular degeneration, beta carotene with lung cancer, ly-copene with prostate cancer, and all the major circulating carotenoids with CHD.
      • Institute of Medicine
      • Food and Nutrition Board
      The amount of decrease in the serum carotenoid levels caused by plant stanols and sterols should be viewed in the context of other dietary factors that influence circulating levels. Coconsumption with wheat bran significantly inhibits lycopene and lutein absorption.
      • Riedl J
      • Linseisen J
      • Hoffmann J
      • Wolfram G
      Some dietary fibers reduce the absorption of carotenoids in women.
      Volunteers who consumed olestra (8 g/d) had 38% lower levels of beta carotene than did controls after 8 weeks.
      • Schlagheck TG
      • Riccardi KA
      • Zorich NL
      • Torri SA
      • Dugan LD
      • Peters JC
      Olestra dose response on fat-soluble and water-soluble nutrients in humans.
      In addition, some lipid-lowering drugs (probucol and cholestyramine) cause decreases in beta carotene levels beyond what would be expected from the LDL-lowering effects of the drugs alone.
      • Elinder LS
      • Hadell K
      • Johansson J
      • et al.
      Probucol treatment decreases serum concentrations of diet-derived antioxidants.
      Epidemiological studies cannot determine whether the associations between various carotenoids and disease outcomes are causal or due to confounding factors. Several randomized trials have tested the effects of supplemental beta carotene on cancer and CHD.
      • Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group
      The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers.
      • Greenberg ER
      • Baron JA
      • Karagas MR
      • et al.
      Mortality associated with low plasma concentration of beta carotene and the effect of oral supplementation.
      • Omenn GS
      • Goodman GE
      • Thornquist MD
      • et al.
      Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease.
      • Hennekens CH
      • Buring JE
      • Manson JE
      • et al.
      Lack of effect of long-term supplementation with beta carotene on the incidence of malignant neoplasms and cardiovascular disease.
      • Lee IM
      • Cook NR
      • Manson JE
      • Buring JE
      • Hennekens CH
      Beta-carotene supplementation and incidence of cancer and cardiovascular disease: the Women's Health Study.
      These trials show no benefit and in smokers show evidence of harm.
      • Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group
      The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers.
      • Omenn GS
      • Goodman GE
      • Thornquist MD
      • et al.
      Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease.
      This weakens the case for beta carotene as a chemopro-tective agent. Still, it is unclear whether supplement trials are relevant to predicting the effect of reductions in plasma carotenoid induced by stanols and sterols.
      Part of these reductions are due to decreases in circulating LDL levels, which are the carriers for fat-soluble vitamins. In 2 large primary prevention trials using statins (each averaging about 5 years of follow-up), large reductions in LDL levels were not associated with an increase in any cancer.
      • Shepherd J
      • Cobbe SM
      • Ford I
      • West of Scotland Coronary Prevention Study Group
      • et al.
      Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia.
      • Downs JR
      • Clearfield M
      • Weis S
      • et al.
      Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS: Air Force/Texas Coronary Atherosclerosis Prevention Study.
      The effects of these drugs on carotenoid levels have not been reported; thus, the interpretation of these trials with respect to carotenoid lowering is somewhat speculative.
      Cholestyramine, a bile acid sequestering resin, reduces circulating carotenoid levels in excess of the decrease expected due to LDL lowering. In the Lipid Research Clinics Coronary Primary Prevention Trial,
      Lipid Research Clinics Coronary Primary Prevention Trial results, 1: reduction in incidence of coronary heart disease.
      total carotenoid levels decreased 26% in 3806 men after 1 year of intervention compared with a 19% decrease in LDL levels. Despite this large reduction in carotenoid levels, the reduction in coronary events was exactly that which would have been predicted by the changes in serum lipids.
      Lipid Research Clinics Coronary Primary Prevention Trial results, II: the relationship of reduction in incidence of coronary heart disease to cholesterol lowering.
      Although the trial was underpowered for cancer end points, the on-trial (up to 10 years of follow-up) and posttrial (6 additional years of follow-up) experience showed a slight decrease in carot-enoid-linked cancers in the intervention group relative to the placebo group.
      • Lipid Research Clinics Investigators
      The Lipid Research Clinics Coronary Primary Prevention Trial: results of 6 years of post-trial follow-up.
      In summary, risks associated with decreased carotenoid levels secondary to sterol/stanol intake are theoretical at this point, but longer follow-up of studies would be desirable to fully address this issue.

       Do Sterols and Stanols Interfere With the Absorption and Action of Therapeutic Drugs, Including Hormones?

      Information is limited about sterol/stanol interference with the absorption and action of therapeutic drugs. An 8-week study of 318 subjects reported no adverse interactions of stanol intake with drugs.
      • Nguyen TT
      • Dale LC
      • von Bergmann K
      • Croghan IT
      Cholesterol-lowering effect of stanol ester in a US population of mildly hypercholesterolemic men and women: a randomized controlled trial.
      In patients with diabetes, stanols had no effect on diabetic control.
      • Gylling H
      • Miettinen TA
      Serum cholesterol and cholesterol and lipoprotein metabolism in hypercholesterolaemic NIDDM patients before and during sitostanol ester-margarine treatment.
      Stanols and sterols might theoretically interfere with cyclosporine absorption; further studies are needed. Few patients take cyclosporine, and levels are closely monitored. However, transplantation units should be aware of this potential interaction.

       Could Stanols and Sterols or Their Metabolites Have Adverse Effects in the Colon?

      Consumption of plant sterols and stanols increases the fecal excretion of cholesterol and its metabolites. Hypotheses were advanced in the 1960s and 1970s that bacterial metabolites of bile acids and cholesterol were involved in the genesis of colon cancer.
      • Drasar BS
      • Hill MJ
      Intestinal bacteria and cancer.
      Toxicologic animal tests on this subject were discussed previously. Other experiments in vitro and in animals with chemically induced cancers suggested that dietary plant sterols may protect against colon, breast, and prostate cancer.
      • Wilt TJ
      • MacDonald R
      • Ishani A
      Beta-sitosterol for the treatment of benign prostatic hyperplasia: a systematic review.
      • Awad AB
      • Fink CS
      Phytosterols as anticancer dietary components: evidence and mechanism of action.
      However, a prospective study in humans did not support any protective effect of plant sterols against colon or rectal cancer.
      • Normen AL
      • Brants HA
      • Voorrips LE
      • Andersson HA
      • van den Brandt PA
      • Goldbohm RA
      Plant sterol intakes and colorectal cancer risk in the Netherlands Cohort Study on diet and cancer.
      Thus, there are no convincing data to suggest that plant stanols and sterols either contribute to or prevent colon carcinogenesis.

       What Is the Safe Upper Level of Intake of Stanols and Sterols? Is This Level Likely to Be Exceeded in Practice?

      The evidence summarized previously suggests that intake of the recommended 2 g/d of sterols and stanols effectively lowers LDL cholesterol levels, produces no serious adverse effects, and poses no health risks of concern. Some consumers might reach higher intake levels if they consume a wide range of products enriched with stanols and sterols. There is no evidence that such higher intakes cause harm. However, increasing intake beyond 2 g/d of stanols and sterols produces little additional LDL lowering and therefore is not recommended.

      RECOMMENDED FUTURE RESEARCH

       Who Consumes Sterol/Stanol Products and What Is Their Effectiveness in the General Population?

      In a Finnish survey,
      • Anttolainen M
      • Luoto R
      • Uutela A
      • et al.
      Characteristics of users and nonusers of plant stanol ester margarine in Finland: an approach to study functional foods.
      46% of people who used plant stanol ester margarine reported having cardiovascular disease. Users were mostly aged 55 years or older, were better educated, and had higher incomes than nonusers. They also had a healthier lifestyle. No data are available on the initial cholesterol levels of the users or on the extent of cholesterol lowering obtained when sterol-and stanol-rich foods were introduced into communities. Therefore, the effectiveness (efficacy multiplied by compliance) of sterols and stanols in the general population is still unclear.

       Is Postmarketing Surveillance (Postlaunch Monitoring) Being Done, and Is It Useful for Detecting Unforeseen Effects?

      About 2500 users of stanol margarines and matched controls are being followed up in Finland, and possible long-term health effects, both beneficial and adverse, will be determined by linking national disease and mortality registries with the cohort.
      • Anttolainen M
      • Luoto R
      • Uutela A
      • et al.
      Characteristics of users and nonusers of plant stanol ester margarine in Finland: an approach to study functional foods.
      Although valuable, this study probably has limited power to detect rare adverse effects. The nonrandomized design also introduces confounding, difficult to avoid in observational studies. Telephone help lines have been installed and are monitored for self-reported adverse effects of stanol and sterol margarines.

       Is a Trial With Hard End Points (Disease and Death) Required?

      A randomized clinical trial might provide certainty about the efficacy of stanols and sterols in reducing CHD. The costs and feasibility of a such a trial are prohibitive, as they have been for other dietary factors. The numbers of CHD patients needed to show the expected 12% to 20% reduction in CHD over 5 years would be 10,000 to 15,000. In healthy subjects, event rates are lower and required numbers proportionally higher. For example, with a 6% reduction in total cholesterol (corresponding to a 9% reduction in LDL cholesterol), close to 50,000 postmenopausal women might need to be randomized and followed up for 9 years to show the expected reduction of 14% in CHD at a power of 86%.
      • LaRosa JC
      • He J
      • Vupputuri S
      Effect of statins on risk of coronary disease: a meta-analysis of randomized controlled trials.
      • Women's Health Initiative Study Group
      Design of the Women's Health Initiative clinical trial and observational study.
      Moreover, such a trial would not provide total reassurance about the absence of long-term adverse effects because they are likely to be rare, and a clinical trial would be severely underpowered to detect them.
      Trials with surrogate end points could be used to corroborate the expected efficacy for cardiovascular disease prevention. The most convincing surrogate outcome would be a decrease in the progression of intima-media thickness of the carotid artery, and some workshop participants believe that initiating such a trial would be useful. However, most agree that current evidence is sufficient to encourage use of sterols and stanols.

      CONCLUSIONS

      Abundant evidence shows that consuming 2 g/d of sterols and stanols lowers LDL levels by 10%, and based on epi-demiological data and trials with cholesterol-lowering drugs, long-term use likely will lower CHD risk by 12% to 20% in the first 5 years and by 20% over a lifetime. Safety testing of sterols and stanols has exceeded that of ordinary foodstuffs that are eaten widely and generally recognized as safe. Adverse effects of the absorption of plant sterols into the circulation appear largely hypothetical in adults. Adverse health outcomes due to observed decreases in beta carotene levels in plasma are speculative and are of no major concern. Safety is being monitored by follow-up of samples from the general population eating these foods; however, the power of such studies to detect rare adverse effects, if any exist, is limited. A clinical trial would be extremely expensive and would probably not answer remaining questions about infrequent adverse effects. Trials with surrogate end points such as intima-media thickness might corroborate the expected efficacy of stanols and sterols in reducing the progression of atherosclerosis. However, current evidence is already sufficient to encourage use of sterols and stanols in persons with elevated cholesterol who are at increased risk for CHD.
      We thank Dianora Feretti and Daniela Galli for their crucial role in organizing the workshop and Rianne Hermus for organizational and administrative support. We gratefully acknowledge the important contributions of Drs Nilo Cater, Andrea Poli, Paul Hepburn, Stephen Kritchevsky, Ronald Mensink, Joan Morris, Jogchum Plat, and Jacques Rossouw to this article.
      Stresa Workshop on Sterols and Stanols.—Workshop participants: Atif B. Awad, University at Buffalo, Buffalo, NY; Klaus von Bergmann, University of Bonn, Bonn, Germany; Nilo Cater, Southwestern Medical Center, University of Texas, Dallas; Jiri Frohlich, St Paul's Hospital and University of British Columbia, Vancouver, British Columbia; Helena Gylling, University of Kuopio, Kuopio, Finland; Paul A. Hepburn, Safety & Environmental Assurance Centre Unilever, Sharnbrook, United Kingdom; Thomas E. Kottke, Mayo Clinic, Rochester, Minn; Stephen B. Kritchevsky, University of Tennessee, Memphis; Gilbert A. Leveille, McNeil Consumer Healthcare, Fort Washington, Pa; Gert W. Meijer, Unilever Bestfoods NA, Englewood Cliffs, NJ; Ronald P. Mensink, Maastricht University, Maastricht, the Netherlands; Mohammed H. Moghadasian, University of British Columbia, Vancouver, British Columbia; Paul Nestel, Baker Medical Research Institute, Melbourne, Australia; Fady Y. Ntanios, Unilever Health Institute, Vlaardingen, the Netherlands; Richard E. Ostlund, Washington University Medical School, St Louis, Mo; Vieno I. Piironen, University of Helsinki, Helsinki, Finland; Andrea Poli, Nutrition Foundation of Italy, Milan; Pekka Puska, World Health Organization, Geneva, Switzerland; Jacques E. Rossouw, National Heart, Lung, and Blood Institute, Bethesda, Md; Gerald Salen, New Jersey Medical School, Newark; Olli Simell, University of Turku, Turku, Finland; Michihiro Sugano, Prefectural University of Kumamoto, Kumamoto, Japan; Matti Uusitupa, University of Kuopio and Kuopio University Hospital, Kuopio, Finland; Bengt Vessby, University of Uppsala, Uppsala, Sweden; Ingmar Wester, Raisio Group, Raisio, Finland; and Jan A. Weststrate, Unilever Health Institute, Vlaardingen, the Netherlands.

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