Background Dietary plant sterols, especially sitostanol, reduceserum cholesterol by inhibiting cholesterol absorption. Solublesitostanol may be more effective than a less soluble preparation.We tested the tolerability and cholesterol-lowering effect ofmargarine containing sitostanol ester in a population with mildhypercholesterolemia.
Methods We conducted a one-year, randomized, double-blind studyin 153 randomly selected subjects with mild hypercholesterolemia.Fifty-one consumed margarine without sitostanol ester (the controlgroup), and 102 consumed margarine containing sitostanol ester(1.8 or 2.6 g of sitostanol per day).
Results The margarine containing sitostanol ester was well tolerated.The mean one-year reduction in serum cholesterol was 10.2 percentin the sitostanol group, as compared with an increase of 0.1percent in the control group. The difference in the change inserum cholesterol concentration between the two groups was -24mg per deciliter (95 percent confidence interval, -17 to -32;P<0.001). The respective reductions in low-density lipoprotein(LDL) cholesterol were 14.1 percent in the sitostanol groupand 1.1 percent in the control group. The difference in thechange in LDL cholesterol concentration between the two groupswas -21 mg per deciliter (95 percent confidence interval, -14to -29; P<0.001). Neither serum triglyceride nor high-densitylipoprotein cholesterol concentrations were affected by sitostanol.Serum campesterol, a dietary plant sterol whose levels reflectcholesterol absorption, was decreased by 36 percent in the sitostanolgroup, and the reduction was directly correlated with the reductionin total cholesterol (r = 0.57, P<0.001).
Conclusions Substituting sitostanol-ester margarine for partof the daily fat intake in subjects with mild hypercholesterolemiawas effective in lowering serum total cholesterol and LDL cholesterol.
Plant sterols, including sitosterol, stigmasterol, and campesterol,are present in the Western diet in an amount almost equal todietary cholesterol intake — that is, 160 to 360 mg perday.1 Since the 1950s, large amounts of these sterols, mainlysitosterol, have been added to patients' diets for the treatmentof hypercholesterolemia.2,3,4,5,6 Plant sterols inhibit cholesterolabsorption, but the resulting decrease in serum cholesterolhas only been slight.4,5,6,7 Sitostanol, a 5-saturated sitosterolderivative, reduces the intestinal absorption of cholesteroland serum cholesterol more effectively than does sitosterol.8,9,10In addition, sitostanol is virtually unabsorbable and otherplant sterols are absorbed only in very small amounts, so thatthe serum concentration of plant sterols is less than 1 percentof the respective cholesterol value.1 The cholesterol-loweringeffect of sitostanol may be increased when it is ingested ina soluble form.11 Therefore, a margarine rich in sitostanolester has been developed and has been shown to reduce cholesterollevels and to be well tolerated in preliminary short-term studieswhen used to replace a part of the daily fat consumption.11,12,13,14We designed the present study to investigate the long-term tolerabilityand cholesterol-lowering effect of this margarine in a randomlyselected, mildly hypercholesterolemic population sample.
Methods
The subjects were recruited from a random population sampleof about 1500 people from the province of North Karelia, Finland.Six months earlier, concentrations of serum total and high-densitylipoprotein (HDL) cholesterol and triglycerides had been measuredin the subjects in the Finrisk '92 study.15 The primary selectioncriteria were as follows: serum cholesterol concentration, >216mg per deciliter (5.58 mmol per liter); triglyceride concentration,<265 mg per deciliter (3.0 mmol per liter); age between 25and 64 years; body-mass index (the weight in kilograms dividedby the square of the height in meters), <30; stable medicationfor hypertension, diabetes, or coronary heart disease; and theabsence of renal, alcohol, liver, or thyroid problems. On thebasis of these criteria, 153 subjects were accepted as participantsin the study. Men accounted for 42 percent of the population.The subjects volunteered for the study, and the study protocolwas approved by the Ethics Committee of the Second Departmentof Medicine, University of Helsinki.
After a blood sample was taken with the subjects fasting, theywere advised to replace 24 g per day of their normal dietaryfat for six weeks with a margarine containing rapeseed oil,according to careful instructions from a qualified nurse. Thepercentages of the major fatty acids in the margarine were 16:0= 16.7 percent, 18:1 = 47.3 percent, 18:2 = 17.7 percent, and18:3 = 8.9 percent. The total amount of trans fatty acids was0.5 percent. The margarine was provided in containers that wereintended to hold 8 g each; the actual weight of the margarinein a container, as measured at various times during the study,ranged from 7.3 to 7.7 g. The participants used one containerof margarine, usually on a slice of bread, at each breakfast,lunch, and dinner.
The sitosterol-ester margarine contained 1 g of sitostanol per8-g portion. The preparation of this margarine involved artificiallysaturating sitosterol, a product of the wood industry, to createsitostanol; the ester form was prepared by transesterificationof free sitostanol with rapeseed oil (Raisio Inc., Raisio, Finland).11,12,13At the end of the six-week period, the subjects were randomizedso that one group (51 subjects) continued to use rapeseed-oilmargarine without added sitostanol for a year, and the othergroup (102 subjects) used the same margarine with added sitostanolester so that the daily intake of free sitostanol would be 3g per day. Randomization was stratified according to sex. Aftera six-month period, members of the sitostanol-ester group wererandomly reassigned either to continue their intake of 3 g ofsitostanol per day (51 subjects) or to reduce their intake to2 g per day (51 subjects), with the intake of margarine subsequentlykept unchanged for the remaining six months. The subjects werenot informed of this change in sitostanol intake. The mean (±SE)body weights in the three randomized groups (72±2, 71±2,and 70±1 kg) and mean ages (51±1, 49±2,and 51±1 years) were similar. After the 12-month studyperiod, the subjects switched back to their regular base-line,ad libitum diet. Blood samples were taken twice, one week apart,at month 0 (at the end of the 6-week period during which controlmargarine was used), at 12 months (at the end of treatment),and at 14 months (after treatment), as well as once 11/2 monthsbefore and 3, 6, and 9 months after month 0. The post-treatmentblood samples were obtained to measure the subjects' lipid valuesafter they resumed their base-line, ad libitum diet.
During each study visit, the subjects filled out questionnairesdesigned to determine whether they could distinguish differencesin the taste, texture, spreadability on bread, and side effects,if any, of the margarines with sitostanol and without it. Bodyweight was measured when each blood sample was taken. The intakeof margarine was confirmed by the number and emptiness of thecontainers (the subjects were advised to return all containers);the difference in weight between the delivered and the returnedcontainers was the measure of adherence to the study regimen.Seven-day food diaries were kept by one third of each groupat 9 months and at the end of 14 months.
Serum total cholesterol, HDL cholesterol, and triglycerideswere measured automatically with the use of commercial kits(Boehringer–Ingelheim, Ingelheim, Germany). The concentrationsof low-density lipoprotein (LDL) cholesterol were calculatedaccording to the methods of Friedewald et al.16 Serum campesterolconcentrations, known to reflect cholesterol absorption,1,17were quantified with gas–liquid chromatography from nonsaponifiablecomponents of serum lipids on a 35-m capillary SE-30 column.1,18The means of two measurements of serum lipids were calculatedbefore the subjects started eating sitostanol-ester margarine,at the end of the 12-month study, and 2 months after the studyended.
Analysis of variance for repeated measurements was used forthe hypothesis testing. P values are given for the interactionbetween time and the study groups. The 95 percent confidenceintervals for the differences in the changes between the groupsare also given.19 Statistical analyses were performed accordingto the intention to treat.
Results
The body weights of the patients in the three groups were similarat base line and did not change consistently during the study.Dietary cholesterol intakes were similar in the three groupsduring the study and did not change detectably from those ofthe post-study ad libitum diet (Table 1). The percentages ofenergy derived from dietary fat and from saturated, monounsaturated,and polyunsaturated fatty acids were also similar throughoutthe study in the three groups. The return to the post-studyad libitum diet reduced the intake of monounsaturated and polyunsaturatedfatty acids (Table 1). The ratio of mean values for polyunsaturatedfatty acids to mean values for saturated fatty acids rangedfrom 0.46 to 0.43 among the three groups during the study, anddecreased to a range of 0.42 to 0.32 with the poststudy ad libitumdiet.
Table 1. Dietary Intake of Cholesterol and Fatty Acids in the Three Study Groups on the Study Diet and Post-study Ad Libitum Diet.
No side effects were reported on the questionnaires, and thespreadability of the margarines on bread was reported to besimilar in the three groups. After the first randomization,19 and 30 percent of the two groups consuming sitostanol-estermargarine (calculated retrospectively) reported a change intaste, whereas 10 percent of the control-margarine group (P= 0.051) reported such a change. After the second randomization,in which sitostanol intake was decreased in a third of the subjectsfrom 3 g per day to 2 g, the respective percentages were 15,18, and 10 (P = 0.54). The compliance was very good, with only12 subjects (8 percent) dropping out: 3 during the first, six-week,control-margarine period (these subjects were included in theintention-to-treat analysis); 3 from the control-margarine group;and 6 from the two sitostanol groups. The daily consumptionof the margarines was similar among the groups after the firstrandomization (19.2 to 20.0 g per day) and after the second(19.0 to 19.2 g per day). The patients consumed 86 percent ofthe 22.5 g of margarine per day that was delivered. Measurementof sitostanol in the margarine and the actual intake of themargarine showed that the mean sitostanol intake was 2.6 and1.8 g per day in the two sitostanol groups.
Serum Lipids
The base-line lipid levels were similar among the three groups(Table 2). The use of the control margarine for 6 weeks andfor the additional year did not change the serum concentrationsof total, LDL, or HDL cholesterol or of triglycerides, but itwas followed by a significant increase in these serum concentrationswith the post-study ad libitum diet at 12 to 14 months (Table 2and Figure 1).
Figure 1. Serum Cholesterol Levels before and after the Consumption of Margarine with and without Sitostanol Ester for 12 Months.
All three groups consumed a base-line ad libitum diet for 11/2 months before the study and from 12 to 14 months after the start of the study. Control margarine was consumed by all three groups for 11/2 months before the study began and by the control group (•) from month 0 to month 12. At six months, the sitostanol group of 102 subjects was divided into two subgroups of 51 subjects each. The subgroup that consumed 2.6 g of sitostanol per day is indicated by the squares, and the subgroup that consumed 1.8 g of sitostanol per day is indicated by the triangles. To convert values for cholesterol to millimoles per liter, multiply by 0.026.
The addition of sitostanol ester (2.6 g per day) to the margarinedecreased serum cholesterol by 7.4 percent and LDL cholesterolby 10.4 percent at 6 months, and by 10.2 percent and 14.1 percent,respectively, at 12 months (Table 2). The respective changesin the control group were +0.7 percent and +0.9 percent at 6months, and +0.1 percent and -1.1 percent at 12 months. Duringthe 12-month interval, serum cholesterol decreased 24 mg perdeciliter more in the group consuming 2.6 g of sitostanol margarineper day than in the control group (95 percent confidence interval,-17 to -32) (Table 3). The difference in change between thetwo groups was statistically significant (P<0.001), as calculatedby analysis of variance for repeated measurements. The differencein the serum LDL cholesterol concentration between these groupswas -21 mg per deciliter (95 percent confidence interval, -14to -29).
Table 3. Mean Changes in Serum Lipid Concentrations and HDL:LDL Cholesterol Ratios among Subjects Who Completed the 12-Month Study.
The reduction in sitostanol intake to 1.8 g per day at six monthswas not accompanied by any further decrease in the LDL cholesterolconcentrations during the next six months (in fact, there wasan increase of 1 mg per deciliter), whereas a reduction of 7mg per deciliter was seen in the group consuming 2.6 g of sitostanol(Table 2). The difference in change between the two sitostanolgroups was -8 mg per deciliter (95 percent confidence interval,-28 to 0). Thus, a statistically significant difference (P =0.017) can be seen between the 6th and 12th months in the LDLcholesterol curves for the two groups. The respective changesin serum total cholesterol concentration were +3 mg per deciliterin the group consuming 1.8 g of sitostanol, and -5 mg per deciliterin the group consuming 2.6 g (Table 2 and Figure 1). The differencein change between the groups was -8 mg per deciliter (95 percentconfidence interval, -17 to 1; P = 0.047). When subjects resumedtheir ad libitum diet after the study, the values returned toinitial levels in both groups.
Serum HDL cholesterol and triglyceride concentrations were notaffected by the consumption of sitostanol ester (Table 2 andTable 3). Thus, the ratio of HDL cholesterol to total cholesterolwas increased by 12.5 percent in the sitostanol group at oneyear, as compared with an increase of 1.6 percent in the control-margarinegroup. The respective increases in the ratio of HDL to LDL cholesterolwere 20.3 percent and 4.4 percent. The differences between thegroups in the changes in both ratios were significant (P<0.001).The sitostanol-ester–induced reductions in the concentrationsof total and LDL cholesterol were inversely related to the respectivepre-sitostanol values (r = -0.40 and r = -0.39, P<0.001 forboth) but not to the dietary intake of cholesterol.
Margarine with sitostanol markedly reduced the serum campesterolconcentration. Thus, at six months the value had decreased 36.5percent from the pre-sitostanol level of 694±41 µgper deciliter (18.6±1.1 µmol per liter) to 399±19µg per deciliter (10.7±0.5 µmol per liter).In the control-margarine group, the respective change was +2.0percent. The difference in the changes between the two groupswas significant (P<0.001). The higher the decrease in theserum campesterol concentration, the higher the pre-sitostanolconcentration of campesterol (r = -0.47, P<0.001) and thegreater the fall in the total cholesterol concentration (r =0.57, P<0.001), as shown in Figure 2. The base-line campesterolconcentration was significantly related to the serum cholesterolvalues (r = 0.27, P<0.01). However, the correlation coefficientof the relation between the change in the ratio of campesterolto cholesterol and the change in serum cholesterol was 0.55(P<0.001).
Figure 2. Correlation of Changes in the Total Cholesterol Concentration with Those in the Campesterol Concentration after the Consumption of 2.6 g of Sitostanol-Ester Margarine per Day for Six Months (r = 0.57, P<0.001).
To convert values for cholesterol to millimoles per liter, multiply by 0.026.
Discussion
Margarine fortified with sitostanol ester decreased serum totaland LDL cholesterol concentrations by about 10 to 14 percentin the subjects with mild hypercholesterolemia in our randomlyselected population sample. In the taste-test comparisons, itwas possible to distinguish the substituted margarine, whichreplaced almost one fifth of the daily fat consumed, from themargarine without sitostanol ester, but the participants couldnot decide which of the two tasted better. The dropout ratewas small (8 percent) and was similar in all groups.
The decrease in the total cholesterol concentration occurredmainly during the three first months, but even after three monthsthe values tended to continue falling (Figure 1) with continueddietary sitostanol intake. Thus, earlier preliminary studies,which were conducted for up to six weeks, may have been tooshort to show the full decrease in total cholesterol values.11,12,13,14Despite the finding that the decreasing trends between the 6thand 12th months in the total and LDL cholesterol concentrationsin the group consuming 2.6 g of sitostanol were slightly butsignificantly different from the increasing trends in the groupconsuming 1.8 g, for practical purposes the two doses producedsimilar cholesterol-lowering effects. According to epidemiologicstudies, a 14 percent decrease in the serum LDL cholesterolconcentration would decrease the incidence of coronary heartdisease by approximately one third.20
Campesterol is a dietary plant sterol not synthesized in thebody, and it is absorbed to such a small extent that its serumconcentration is less than 1 percent of the cholesterol value.1The serum concentration of campesterol was measured becauseit reflects intestinal cholesterol absorption in humans.1,17Thus, the lower the campesterol value, the lower the percentageof intestinal cholesterol that is absorbed.
The marked fall in the campesterol values by 36 percent duringthe study period indicates that sitostanol ester decreased theintestinal absorption of cholesterol. The fall in the cholesterolvalues was relatively smaller because, in contrast to the waythe body responds to campesterol, the decreased absorption ofcholesterol apparently induced a compensatory increase in cholesterolsynthesis, so that the decrease in the LDL cholesterol levelwas markedly less than the decrease in campesterol. Previousshort-term studies have shown that treatment with sitostanolester stimulates cholesterol synthesis11,12,13,14 and inhibitscholesterol absorption by about 60 percent in patients withdiabetes.13 The positive correlation between the changes inthe total cholesterol and campesterol concentrations (or inthe campesterol-to-cholesterol ratio) suggests that in the patientswho did not respond, the unchanged cholesterol concentrationwas associated with unchanged cholesterol absorption, as reflectedin the unchanged campesterol value; in the patients with thestrongest responses, the decreases in the campesterol concentration(or the campesterol-to-cholesterol ratio) were greatest.
Since the mechanism by which dietary sitostanol-ester margarinereduces serum cholesterol is the inhibition of cholesterol absorption,questions arise about whether the absorptions of dietary andof biliary cholesterol were similar, and whether the absorptionof fat-soluble vitamins was also decreased. Earlier studiesin humans suggest that dietary plant sterols inhibit the absorptionof dietary cholesterol more effectively than the absorptionof biliary cholesterol.21 The relatively high dietary cholesterolconcentrations (mean, 282 to 340 mg per day) may have contributedto the favorable results presented here. A weak response ofserum cholesterol concentrations to dietary sitostanol intakein a recent study may have been explained by the fact that dietarycholesterol intake was low.22 In our preliminary analyses, noconsistent change in serum antioxidant concentrations was detectableduring a short-term study, as indicated by measurement of -tocopherolor -carotene.13 In addition, the 12-month change in serum -tocopherolconcentrations (-1.3±1.2 mg per liter in the sitostanolgroup and 1.6±0.9 mg per liter in the control group)was similar in the present study in spite of the markedly loweredLDL cholesterol concentrations in the sitostanol group. DecreasedLDL oxidation has been suspected to be an antiatherogenic factor.23Thus, combining margarine with sitostanol ester could be a beneficialdietary measure to eliminate harmful effects of LDL in the developmentof coronary disease.
Our findings suggest that long-term use of sitostanol-estermargarine as a substitute for part of normal dietary fat hasfavorable effects. Sitostanol itself is not absorbed and doesnot appear to interfere detectably with the absorption of fat-solublevitamins. It is tasteless, and it can be added to relativelysmall amounts of dietary fat in sufficiently large amounts tocause a moderate decrease of cholesterol. Thus, our study suggeststhat the substitution of sitostanol-ester margarine for a portionof normal dietary fat is suitable as a strategy to reduce serumcholesterol in the population.
Source Information
From the Department of Medicine, Division of Internal Medicine, University of Helsinki (T.A.M., H.G., H.V.), and the Department of Epidemiology and Health Promotion, National Public Health Institute (P.P., E.V.) — both in Helsinki, Finland.
Address reprint requests to Dr. Miettinen at the Department of Medicine, Division of Internal Medicine, University of Helsinki, Haartmaninkatu 4, FIN-00290 Helsinki, Finland.
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Kwiterovich, P. O. Jr., Chen, S. C., Virgil, D. G., Schweitzer, A., Arnold, D. R., Kratz, L. E.
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Vanstone, C. A, Raeini-Sarjaz, M., Parsons, W. E, Jones, P. J.
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Amundsen, A. L, Ose, L., Nenseter, M. S, Ntanios, F. Y
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Nissinen, M., Gylling, H., Vuoristo, M., Miettinen, T. A.
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Herron, K. L., Vega-Lopez, S., Conde, K., Ramjiganesh, T., Roy, S., Shachter, N. S., Fernandez, M. L.
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Franz, M. J., Bantle, J. P., Beebe, C. A., Brunzell, J. D., Chiasson, J.-L., Garg, A., Holzmeister, L. A., Hoogwerf, B., Mayer-Davis, E., Mooradian, A. D., Purnell, J. Q., Wheeler, M.
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Nicolosi, R. J., Wilson, T. A., Lawton, C., Handelman, G. J.
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Volger, O. L., van der Boom, H., de Wit, E. C. M., van Duyvenvoorde, W., Hornstra, G., Plat, J., Havekes, L. M., Mensink, R. P., Princen, H. M. G.
(2001). Dietary Plant Stanol Esters Reduce VLDL Cholesterol Secretion and Bile Saturation in Apolipoprotein E*3-Leiden Transgenic Mice. Arterioscler. Thromb. Vasc. Bio.
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Gardner, C. D, Newell, K. A, Cherin, R., Haskell, W. L
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Lichtenstein, A. H., Deckelbaum, R. J.
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Krauss, R. M., Eckel, R. H., Howard, B., Appel, L. J., Daniels, S. R., Deckelbaum, R. J., Erdman, J. W. Jr, Kris-Etherton, P., Goldberg, I. J., Kotchen, T. A., Lichtenstein, A. H., Mitch, W. E., Mullis, R., Robinson, K., Wylie-Rosett, J., St. Jeor, S., Suttie, J., Tribble, D. L., Bazzarre, T. L.
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Vissers, M. N, Zock, P. L, Meijer, G. W, Katan, M. B
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Krauss, R. M., Eckel, R. H., Howard, B., Appel, L. J., Daniels, S. R., Deckelbaum, R. J., Erdman, J. W. Jr, Kris-Etherton, P., Goldberg, I. J., Kotchen, T. A., Lichtenstein, A. H., Mitch, W. E., Mullis, R., Robinson, K., Wylie-Rosett, J., St. Jeor, S., Suttie, J., Tribble, D. L., Bazzarre, T. L.
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[Abstract][Full Text]
-saturated sitosterol derivative, reduces the intestinal absorption of cholesterol and serum cholesterol more effectively than does sitosterol.8,9,10 In addition, sitostanol is virtually unabsorbable and other plant sterols are absorbed only in very small amounts, so that the serum concentration of plant sterols is less than 1 percent of the respective cholesterol value.1 The cholesterol-lowering effect of sitostanol may be increased when it is ingested in a soluble form.11 Therefore, a margarine rich in sitostanol ester has been developed and has been shown to reduce cholesterol levels and to be well tolerated in preliminary short-term studies when used to replace a part of the daily fat consumption.11,12,13,14 We designed the present study to investigate the long-term tolerability and cholesterol-lowering effect of this margarine in a randomly selected, mildly hypercholesterolemic population sample. 
-carotene.13 In addition, the 12-month change in serum 
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