Effect of low-fat, fermented milk enriched with plant sterols onserum lipid profile and oxidative stress in moderatehypercholesterolemia1Ϫ3 Boris Hansel, Catherine Nicolle, Florent Lalanne, Franc¸oise Tondu, Taous Lassel, Yves Donazzolo, Jean Ferrières,Michel Krempf, Jean-Louis Schlienger, Bruno Verges, M John Chapman, and Eric Bruckert ABSTRACT
reduce plasma concentrations of LDL cholesterol by Ȃ10% (1).
Background: Plant sterol (PS)-enriched foods have been shown to
Thus, a daily intake of PSs in the range of 1-2 g/d is now recom- reduce plasma LDL-cholesterol concentrations. In most studies, mended for hypercholesterolemic patients (2). Indeed, the hypo- however, PSs were incorporated into food products of high fat cholesterolemic effect of PSs is additive to that of other dietary measures, such as a reduction in saturated fat intake (3). PSs, Objective: We examined the effect of daily consumption of PS-
which closely resemble cholesterol in their molecular structure, supplemented low-fat fermented milk (FM) on the plasma lipid exert their hypocholesterolemic effect primarily through com- profile and on systemic oxidative stress in hypercholesterolemic petitive inhibition of cholesterol micellar solubilization and, hence, of the intestinal absorption of both dietary and biliary Design: Hypercholesterolemic subjects (LDL-cholesterol concen-
trations ͧ130 and ͨ 190 mg/dL; n ҃ 194) consumed 2 low-fat In most previous studies, PSs were incorporated into high-fat portions of FM in the same meal daily for 6 wk. Subjects were foods, such as dressings, margarines, or spreads, to facilitate their randomly assigned to 2 groups: low-fat FM enriched with 0.8 g PS solubility. In a recent meta-analysis, the consumption of Œ2 g/d ester per portion or control FM. Plasma concentrations of lipids, of PS-enriched fat food products reduced LDL-cholesterol con- oxidized LDL, ␤-carotene, ␤-sitosterol, campesterol, and high- centrations by 0.33-0.54 mmol/L (5). Furthermore, it has been sensitivity C-reactive protein were measured during the trial.
suggested that the dispersion of PSs in different food forms may Results: Plasma LDL-cholesterol concentrations were reduced by
substantially affect the degree of LDL cholesterol reduction 9.5% and 7.8% after 3 and 6 wk, respectively, in the 1.6-g/d PS group achieved (1). However, few studies have examined the hypocho- compared with the control group, whereas plasma triacylglycerol lesterolemic effect of PS supplementation in low-fat dairy prod- and HDL-cholesterol concentrations were not significantly affected.
ucts such as milk (6, 7), yogurt (6, 8 –11), and other beverages In addition, there were no significant changes in serum ␤-carotene on normalization to LDL cholesterol during the study period in bothgroups, whereas plasma concentrations of oxidized LDL were re- Atherosclerosis underlies most forms of cardiovascular dis- duced significantly in the PS group compared with the control group ease, and both chronic low-level inflammation and oxidative (Ҁ1.73 compared with 1.40 U/L, respectively; P  0.05). Plasma stress are prominent features of its pathophysiology. Oxidative sitosterol concentrations were increased by 35% (P  0.001 com- stress results from an imbalance between tissue prooxidants (free pared with control); however, campesterol concentrations did not From the Service d’Endocrinologie-Métabolisme, AP-HP, Hôpital de la Conclusion: Daily consumption of 1.6 g PS in low-fat FM effi-
Pitié, Paris, France (BH and EB); Institut National de la Santé et de laRecherche Médicale (INSERM) Unité 551 “Dyslipidemia and Atheroscle- ciently lowers LDL cholesterol in subjects with moderate hypercho- rosis” and University Pierre and Marie Curie, Hôpital de la Pitié, Paris, lesterolemia without deleterious effects on biomarkers of oxidative France (BH, MJC, and EB); Danone Vitapole, Centre de Recherche Daniel Am J Clin Nutr 2007;86:790 – 6.
Carasso, Nutrivaleur, Palaiseau, France (CN, FL, FT, and TL); OPTIMED,Gieres, France (YD); Service de Cardiologie, AP-HP, Centre Hospitalier KEY WORDS
Plant sterol, hypercholesterolemia, oxidative d’Endocrinologie et Nutrition, Hôpital hôtel Dieu, Nantes, France (MK);Service de Médecine Interne, CHU de Hautepierre, Strasbourg, France(J-LS); and Service Endocrinologie, Diabétologie et Maladies Métaboliques, INTRODUCTION
Hôpital du Bocage, Dijon, France (BV).
Elevated concentrations of plasma LDL cholesterol are rec- Supported by a grant from Danone Research (Palaiseau, France).
ognized as a major risk factor for the development of premature Address reprint requests to B Hansel, Service d’Endocrinologie- Métabolisme, Pavillon Benjamin Delessert, Hôpital de la Pitié, 83 boulevard cardiovascular disease. Therapeutic strategies aimed at reducing de l’Hôpital, 75651 Paris Cedex 13, France. E-mail: boris.hansel@ LDL cholesterol focus on dietary recommendations as an initial step. Among these recommendations, the daily consumption of dietary constituents enriched in plant sterols (PSs) was shown to Accepted for publication May 10, 2007.
Am J Clin Nutr 2007;86:790 – 6. Printed in USA. 2007 American Society for Nutrition LOW-FAT PLANT STEROLS IN HYPERCHOLESTEROLEMIA radicals or oxygen reactive species) and antioxidants (enzymes and vitamins; 14). LDL is preferentially deposited in the vascular Clinical and biological characteristics of the subjects at baseline1 wall at sites of endothelial dysfunction early in the course of the development of atherosclerotic lesions, where it is oxidized as a consequence of oxidative stress. Numerous in vitro or animalmodels of human atherosclerosis suggest that oxidized lipids derived from LDL (oxLDL) possess proinflammatory activity and play a major role not only at early stages of atherogenesis, but equally at late stages involving plaque rupture with ensuing clin- ical events (15). Recently, plasma concentrations of oxLDL were shown to be a strong predictor of acute coronary heart disease events (16). The potential effect of daily consumption of PS on the level of oxidative stress remains to be established. It could be speculated that dietary PS supplementation, which can mediate reduction in plasma concentrations of fat-soluble vitamins (5), may lead to global impairment of antioxidative defenses and thus to enhanced oxidative stress. In contrast, because dietary PS consumption leads to a reduction in the plasma concentrations of LDL cholesterol, thereby reflecting a decrease in the number of circulating LDL particles that are susceptible to oxidation, the formation of atherosclerotic lesions is potentially attenuated.
The objectives of the present study were 1) to examine the 1 PS, plant sterol, SBP, systolic blood pressure; DBP, diastolic blood effect of daily consumption of 1.6 g PS in low-fat fermented milk pressure; FBG, fasting blood glucose. Comparisons between the PS-enriched (FM) on the plasma lipid profile in hypercholesterolemic sub- group and the control group were performed by using ANOVA for contin- jects, 2) to quantify the influence of daily intake of PS- uous data or chi-square tests for qualitative data.
supplemented FM on oxidative stress (as assessed by plasma 2 x៮ Ȁ SD (all such values).
concentrations of ␤-carotene and oxLDL) and on inflammation 3 Significantly different from control, P  0.05.
[as assessed by high-sensitivity C-reactive protein (hs-CRP)],and 3) to evaluate the influence of PS consumption on circulating biological characteristics of all subjects (n ҃ 194) are shown in Study design
This double-blind, multicenter (5 centers), parallel (enriched product compared with control), randomized study was stratified Subjects
by statin treatment and consisted of a 4-wk run-in period (general Subjects were recruited from the patient registries at special- dietary recommendations for moderate hypercholesterolemic ized lipid clinical units in several hospitals in France and via patients, exclusion of enriched PS products, and consumption of publicity in local newspapers. The study protocol was carefully 2 low-fat yogurts per day) and a 6-wk experimental phase. At the explained to all subjects before they provided written informed end of the run-in period, the subjects were randomly assigned to consent. The study protocol was approved by the ethics commit- 1 of 2 experimental groups: low-fat FM enriched with 0.8 g PS tee of the Comite Consultatif pour la Protection des Personnes se ester per portion or control FM. Subjects were requested to fol- pretant la Recherche Biomedicale (CCPPRB no. 50-04) in 2004.
low the same dietary recommendations for the next 6 wk and to Subjects were eligible if they were between the ages of 18 and consume 2 low-fat portions of FM daily with the same meal. The 75 y (inclusive), whether they were taking statins (but not other subject flow through the study is shown in Figure 1.
hypocholesterolemic drugs), or whether they were following a Routine laboratory measurements were conducted at the prescribed diet. To be included in the study, subjects had to have screening visit of the study to ensure normal health status. Fasting a serum LDL-cholesterol concentration of 130 –190 mg/dL blood samples were taken 1) at the beginning of the run-in period (3.35– 4.9 mmol/L), a serum triacylglycerol concentration of (day 28) of low-fat FM consumption (day 14), 2) at the beginning 250 mg/dL (2.86 mmol/L), and not have diabetes; normal liver, of the experimental period (day 0), and 3) after 3 and 6 wk (days kidney, and thyroid function and a body mass index (in kg/m2) 21 and 42) of product consumption. Potential side effects were between 19 and 30 were all inclusion criteria. Exclusion criteria were as follows: pregnancy or lactation, change of oral contra-ceptive formulation, the presence of severe disease able to influ- Administration of FM
ence the results (nephritic syndrome or cholestasis), a history of The PS-enriched FM and control FM were produced and pre- cardiovascular disease or chronic inflammatory disease, soy al- pared by Danone Research Center (Palaiseau, France). The com- lergy, and hypersensitivity to milk proteins. On the basis of these positions of the PS-enriched and control products are presented criteria, 365 subjects were eligible; of these, 194 subjects were in Table 2. PSs were extracted from tall oil and were esterified
included in the study and were randomly assigned. One subject with rapeseed oil. The PS-enriched FM contained mainly did not complete the study for personal reasons linked to adverse ␤-sitosterol (75%) and campesterol (8.4%). One serving of FM events not related to the study product. The baseline clinical and supplied 0.8 g PS equivalent as free sterol. Subjects consumed 2 194 randomly assigned
ITT population
191 no deviations or minor deviations
PP population
FIGURE 1. Clinical trial profile. PS, plant sterol; ITT, intention-to-treat; PP, per protocol.
servings to provide a daily dose of 1.6 g PS equivalent as free Descriptive statistics are presented as means Ȁ SDs or as medians and quartiles (with 95% CIs) for continuous data or asa percentage for qualitative variables. Comparisons between the Blood sampling
active group and the control group were performed with statis- Venous blood samples were obtained after the subjects had tical descriptive tests by using a significance level of 5% (2- fasted overnight. Samples were drawn from the forearm vein into sided) with appropriate methods according to the distribution EDTA-treated and plain tubes. Plasma samples were analyzed (parametric or nonparametric or both). The hypocholesterolemic enzymatically for total cholesterol and HDL cholesterol after effect of PS was assessed after 3 and 6 wk of product consump- precipitation of apolipoprotein B– containing lipoproteins (en- tion. Comparisons between 2 groups of continuous data were zymatic colorimetric assay, catalog no. 11491458; Roche Diag- analyzed by using a mixed analysis of variance model (or appro- nostics, Basel, Switzerland); LDL cholesterol was calculated priate nonparametric analysis). Analysis of variance was per- with the use of the Friedewald equation. Plasma concentrations formed on raw data for cholesterol markers and on other markers of ␤-carotene were measured by reversed-phase HPLC. Plasma if departure from normality was not established. In other cases, ␤-sitosterol and campesterol concentrations were measured by statistical analyses were performed on transformed data (loga- gas chromatography–mass spectrometry. The limits of detection rithmic transformation as usually recommended for triacylglyc- and quantification, respectively, ranged from 0.1 and 0.4 ␮g/mL erols or hs-CRP) or on rank data for other markers. Comparisons for sitosterol, from 0.4 and 1.2 ␮g/mL for campesterol, and from between 2 groups of qualitative data were analyzed by using a 0.2 and 0.6 ␮g/mL for lathosterol. hs-CRP concentrations were chi-square or Fisher’s exact test, logistic regression analysis with measured by a particle-enhanced immunoturbidimetric assay a binary response, or a Cochran-Mantel-Haenzel test. For each (Roche). OxLDL was measured with the use of an enzyme im- subject and at each level of stratification, the change from base- munoassay (Mercodia, Uppsala, Sweden). The resultant color line was calculated and expressed in absolute or relative change reaction was read spectrophotometrically at 450 nm.
or both. Statistical analyses were performed on the individualdata by using a general linear model with study product and Compliance
stratification factors (center and statin level). Data analyses wereperformed by using SAS software (version 8.2; SAS Institute Inc, Compliance with the study product was evaluated by inter- viewing the subjects and by counting the unopened and uncon-sumed product packages returned to the clinic. Compliance wasrecorded as the percentage of the scheduled servings consumed.
Noncompliance was defined as the consumption of 80% of the Composition of control and plant sterol (PS)-enriched fermented milk scheduled servings during the study period.
Statistical analyses
The number of subjects was calculated by taking into account a critical difference in LDL cholesterol of 0.32 Ȁ 0.732 mmol/L between the active and the control groups with ␣ ҃ 5% and a power of 80%. Given these constraints, 84 evaluable subjects per group to 168 in total were required. To take into account possible premature withdrawal and block size, a total of 200 subjects was planned to be included for random assignment.
Serum lipid concentrations at baseline and at 3 and 6 wk of intake of the
Study participants
plant sterol (PS)-enriched or control fermented milk and the absolutechange between baseline and the end of the trial (week 6 Ҁ baseline)1 Of the 194 subjects, 3 subjects presented major protocol de- viations (one withdrew prematurely, one had a randomization error, and one had a nonfasting plasma sample at inclusion).
None of the subjects were taking medications that could have affected the results. Given the large number of subjects and the very small number of subjects with major protocol deviations, the analyses were performed on all subjects in the intention-to- There were no significant differences between the PS and the control groups at baseline in age, BMI, systolic and diastolic blood pressures (Table 1), alcohol consumption (46.3% com- pared with 49.5%), and smoking habits (13.7% compared with 14.0%). Men and women were equally distributed in both groups (65% compared with 35% in the active group and 69% compared with 31% in the control group, respectively). Subjects were se- lected on the basis of screening values for mean fasting LDL- cholesterol concentrations between 130 and 190 mg/dL (3.35 and 4.90 mmol/L) and mean triacylglycerol concentrations 250 mg/dL (2.86 mmol/L). The mean plasma concentrations of LDL cholesterol were greater in the group consuming the PS- enriched product than in the control group (158.1 Ȁ 13.4 com- pared with 151.8 Ȁ 15.9 mg/dL, respectively; P  0.05). Neither biological criteria nor dietary habits differed significantly at 1 All values are x៮ Ȁ SD.
baseline. Only 14% and 15% of the control and PS groups, 2 Interaction of study product ҂ time was significant, P  0.001.
respectively, received statin treatment; none of those subjects 3 Comparison between PS-enriched fermented milk group and control discontinued statin treatment during the study. There were no group was performed by using ANOVA on raw data.
significant changes in the dietary habits or levels of physical Significantly different from control: 4P  0.001, 6P  0.01.
5 Absolute change from baseline was calculated for each subject as the activity in either of the groups (data not shown).
end of trial value (week 6) minus baseline value.
7 Interaction of study product ҂ time was not significant: for HDL, P ҃ Compliance and side effects during the study
0.70; for triacylglycerol, P ҃ 0.73.
Compliance for the product enriched in PS and for the control Comparison between PS-enriched fermented milk group and control FM (defined as consumption of Œ80% of the scheduled servings group was performed on log-transformed data by using ANOVA on raw data.
during the study period) was highly satisfactory (95.5%) after 3wk of consumption and attained 97.7% after 6 wk. All subjects and 0.8 Ȁ 1.2%, respectively). The same patterns were observed followed the dietary recommendations. No adverse events re- lated to the consumption of the product occurred during the Plasma total cholesterol concentrations were significantly lower after PS consumption than after consumption of the controlFM (Table 3): Ҁ6.2% reduction at the intermediate visit (P  Serum lipid profile
0.001 between groups) and Ҁ4.7% at the end of the intervention The mean plasma lipid concentrations at baseline and after 3- period (P  0.001 between groups). HDL-cholesterol and and 6-wk consumption of the control FM and of the PS- plasma triacylglycerol concentrations were not significantly af- supplemented FM are shown in Table 3. Most of the reduction
fected by the consumption of the PS-enriched FM (Table 3).
in plasma LDL-cholesterol concentrations was achieved after 3wk. The reduction in LDL cholesterol during the first 3 wk was Plasma plant sterols
9.5% greater in the PS group than in the control group, and it Variation in plasma PS concentrations during the study re- corresponded with a 14.5-mg/dL decrease in LDL cholesterol flected the degree of absorption and transport of PSs in the sys- (P  0.001 between groups). After daily consumption of PS for temic circulation (Table 4). The increase in plasma ␤-sitosterol
3 additional weeks, LDL-cholesterol concentrations were 8.4% concentrations in the PS group was 35% greater than that in the and 0.7% lower than baseline in the PS and control groups, control group at the end of the intervention period (0.81 com- respectively. The mean reduction of LDL cholesterol after daily pared with 0.06 mg/L). There was no significant change in intake of 1.6 g PS was 12.4 mg/dL greater than that in the control plasma campesterol concentrations during the intervention.
group (P  0.001 between groups). After 3-wk consumption of Plasma concentrations of ␤-sitosterol plus campesterol increased the PS-enriched FM, statin-treated and -untreated subjects had significantly more in the PS group (14.5% compared with the LDL-cholesterol concentrations that were reduced by 8.0 Ȁ control group, P  0.001) after the 6-wk intervention period.
2.1% and 8.4 Ȁ 1.2%, respectively. Very little change was ob- Lathosterol is assumed to be a marker of endogenous choles- served in the LDL-cholesterol concentrations of the statin- terol synthesis. Plasma lathosterol concentrations did not differ treated and -untreated subjects in the control group (2.3 Ȁ 3.7% significantly between the 2 groups during the study (Table 4): Plasma plant sterol (PS) and lathosterol concentrations at baseline (week Plasma concentrations of ␤-carotene (absolute and LDL 0) and at the end of the trial (week 6) and the absolute change between cholesterol–adjusted serum concentrations), high-sensitivity C-reactive baseline and the end of the trial (week 6 Ҁ baseline)1 protein (hs-CRP), and oxidized LDL (oxLDL) at baseline and at the end ofthe trial (week 6) and study product effect (week 6 Ҁ baseline)1 1 All values are x៮ Ȁ SD.
2 Comparison between PS-enriched fermented milk group and control group was performed by using ANOVA of rank data.
2 Comparison between the PS-enriched fermented milk group and the 3 Absolute change from baseline was calculated for each subject as control group was performed by using ANOVA of rank data of absolute follows: end of trial value (week 6) Ҁ baseline value.
change. The mean of % change for all subjects is presented.
4 Significantly different from control, P  0.001.
3 x៮ Ȁ SD (all such values).
4, 8 Significantly different from control: 4P  0.001, 8P  0.05.
5 Chi-square test on absolute change, classified into 2 levels: “decreas- Ҁ0.08 compared with Ҁ0.02 mg/L between baseline and week 6 ing” and “stable or increasing.” The mean of % change for all subjects is in the PS and the control groups, respectively; NS.
6 ANOVA of transformed data using logarithmic transformation. The Oxidative stress and inflammation criteria
mean of absolute change for all subjects is presented.
7 Median; lower and upper quartiles in parentheses (all such values).
Absolute and LDL-cholesterol–adjusted ␤-carotene concen- trations are reported in Table 5. The reduction in plasma
␤-carotene concentrations was 12% greater in the PS group than products (17, 18). A meta-analysis (5) showed that daily con- in the control group (P  0.001). However, after standardization sumption of Œ2 g PS in margarines, mayonnaise, butter, or olive for LDL cholesterol, variation in ␤-carotene concentrations dur- oil can reduce LDL-cholesterol concentrations by 0.33-0.54 ing the study did not differ significantly between the 2 groups.
mmol/L in hypercholesterolemic subjects. Few data, however, Plasma concentrations of oxLDL were reduced significantly are available on the plasma cholesterol–lowering properties of more in the group consuming PS (Ҁ1.73 compared with 1.40 nonfat or low-fat PS-enriched foods. Daily consumption of a U/L; P  0.05; Table 5), but the decrease was not significant after relatively low-fat (2%) yogurt containing 1 g PS ester signifi- standardization for LDL cholesterol. hs-CRP was unchanged cantly lowered total cholesterol and LDL-cholesterol concentra- after 6 wk of product consumption, and variation in this variable tions (8); however, in this study, the control FM led to a decrease did not differ significantly between the 2 groups during the study in total cholesterol and LDL-cholesterol concentrations, and comparisons with controls were not available. In a subsequentstudy conducted by Jones et al (13), daily ingestion of 1.8 g freePS in a low-fat beverage failed to decrease LDL-cholesterol DISCUSSION
concentrations in moderately hypercholesterolemic subjects.
In this large, double-blind randomized controlled (PS- The authors hypothesized that the content of fat was not high enriched product compared with control) multicenter study, enough to adequately solubilize phytosterols in the small intes- daily consumption of 1.6 g PS in low-fat FM led to reductions in tine. On the contrary, other studies suggested that relatively low- plasma LDL-cholesterol concentrations of 9.5% and 7.8% in fat dairy products may be an adequate vehicle for the delivery of moderately hypercholesterolemic subjects after 3 and 6 wk, esterified PS to effectively lower plasma cholesterol concentra- tions (6, 9 –11, 19 –21). The LDL-cholesterol reduction found in In previous studies with products naturally containing fat, PSs our study with PS-enriched FM agrees with the latter data. How- were most frequently incorporated in fat-rich vehicles such as ever, in these studies, the vector used to deliver PS was distinct spreads and dressings. Two studies used a naturally fat-free or- (6, 9 –11, 19 –21). First, in the studies of Mensink et al (9) and of ange juice as a vehicle for phytosterol ester and showed an LDL- Doornbos et al (11), the experimental group received a daily cholesterol–lowering effect similar to that of PS-enriched fat intake of 3 g plant stanol esters, ie, about twice the dose of PS LOW-FAT PLANT STEROLS IN HYPERCHOLESTEROLEMIA ingested in our study. In other studies, 2 g PS esters were con- concentrations relative to those of LDL cholesterol, we observed sumed daily. Thus, the dose of PS administered in our protocol that the small decrease in plasma ␤-carotene concentrations did was the lowest among these studies to show a significant de- not reach statistical significance after standardization for LDL- crease in LDL cholesterol when incorporated in a low-fat dairy cholesterol concentrations. These observations are consistent product. Another characteristic of the product tested in the with previous studies (7, 10, 29, 30).
present study is its very low fat content. In previous studies of Oxidative stress, defined as an imbalance between anti- and “low-fat” dairy products (6, 10, 20), the fat content of the prod- prooxidant factors, is implicated in the development of numerous ucts tested was often relatively low but higher than that in the present chronic pathologies, including atherosclerosis. It has been sug- study. The main dietary recommendation for patients with hyper- gested that even a minor decrease in ␤-carotene concentrations cholesterolemia is to limit their intake of saturated fats, including may be proatherogenic. However, antioxidants include numer- those of dairy products. In addition, patients may be reluctant to ous substances or enzymes and liposoluble vitamins that may consume margarine either because they are not in the habit of interact synergistically. Thus, analysis of one component inde- using margarine or because of its taste. Thus, the use of a very- pendently of the others may not accurately reflect their combined low-fat food to administer plant sterols at a sufficient dose is of action and may not, therefore, properly estimate systemic oxi- particular interest in patients with hypercholesterolemia.
dative stress. Thus, we measured the effect of PS on the level of Compliance is obviously a key aspect of therapeutic strategies, oxLDL, an integrative marker of systemic oxidative stress. In all which aim to treat chronic asymptomatic abnormalities. In the likelihood, plasma oxLDL concentrations may depend on the present study, compliance was excellent (reaching 97.7% at the capacity of in vivo antioxidants to protect LDL particles against end of the study), and FM consumption did not give rise to any oxidation in the arterial wall. Plasma concentrations of oxLDL were shown to be a strong predictor of acute coronary heart PS administered in food usually lowers plasma concentrations disease events (16). Interestingly, we report in the present study of LDL cholesterol within a short period of time. In the present that consumption of PS was associated with a significant de- study, the maximum change in LDL cholesterol (Ҁ9.5% com- crease in the plasma concentrations of oxLDL as compared with pared with control) occurred after 3 wk of consumption of PS- the consumption of a control dietary product (P ҃ 0.03). Such a enriched FM. No additional decrease in plasma LDL-cholesterol decrease paralleled the LDL-cholesterol–lowering effect. Thus, concentrations occurred after this period. Nguyen et al (22) re- we interpreted our data to suggest that the slight decrease in ported a similar pattern of response to a spread enriched in plant systemic antioxidant concentrations reported with PS intake did stanol esters, with a maximum change after 2 wk.
not affect LDL oxidation. Our results confirm those of Homma It is well known that lipid and lipoprotein responses to a dietary et al (31), who reported a 20% decrease in oxLDL concentrations change and particularly to sterol- or stanol-enriched products are in patients consuming 2-3 g/d plant stanol in enriched spreads, as heterogeneous (23–25). In our study, 67% of the patients in the sterol group showed a Œ5% decrease in LDL cholesterol. This Another emergent question concerning the therapeutic use of finding suggests that most patients may exhibit a clinically rel- PS has to do with the possibility that their accumulation in plasma evant LDL cholesterol reduction derived from daily consump- may be atherogenic. In our study, plasma PS concentrations, tion of PS-enriched FM in addition to traditional diet recommen- notably, ␤-sitosterol, significantly increased with PS-FM con- sumption (35% compared with control). However, the absolute The effect of PS-enriched margarine in patients taking statins changes in campesterol and ␤-sitosterol concentrations were of a has been shown to be additive rather than synergistic (26). It is small magnitude, and the values in the experimental group were generally assumed that dietary PS esters produce an additional not significantly different from those in patients consuming a reduction in LDL cholesterol of Ȃ6 – 8% (27); the design of our plant food– based diet. For example, in a population of healthy study did not allow us to accurately quantify this additive effect.
pure vegetarians, the plasma concentrations of ␤-sitosterol plus However, the 7.8% LDL-cholesterol–lowering effect of PS- campesterol were similar (6.0 mg/L) to those in patients con- enriched FM was consistent in the subgroup of subjects treated suming PS in our study (5.7 mg/L; 32). Moreover, these values with a statin. Concordantly, we did not observe any interaction are at least one-tenth to one-twentieth those typical of between statin therapy and PS consumption. In line with previous ␤-sitosterolemia, which is characterized by elevated plasma con- results obtained with the use of margarines, the magnitude of the centrations of ␤-sitosterol and accelerated atherosclerosis.
additional decrease in LDL cholesterol is slightly greater than The main weakness of our study is its short duration. However, that to be expected by doubling the dose of statin (28). Unlike PS, a large body of evidence now indicates that reductions in plasma statins inhibit the synthesis of hepatic cholesterol but equally cholesterol induced by PS consumption are sustained over the increase its intestinal absorption. These complementary effects long term, especially when compliance is maintained. In addi- suggest, therefore, that it may be of special interest to combine tion, the low level of adverse effects suggests that PS consump- statin-mediated inhibition of cholesterol synthesis with the inhi- tion is safe over a relatively long period of time (33, 34). Finally, bition of cholesterol absorption by PS in the same subject.
the decrease in hs-CRP observed in patients treated with PS- One of the major concerns with respect to dietary PS supple- enriched FM was not significant, which can be explained by the mentation involves the possibility that fat-soluble vitamin ab- large variability in hs-CRP at baseline and thus a lack of statis- sorption is reduced (5). Because plasma lipoproteins (mainly VLDL and LDL) are the major transport vehicles for lipid- In summary, the present study showed that daily consumption soluble antioxidants, a reduction in LDL concentrations may of 1.6 g PS ester in a very-low-fat PS-enriched FM resulted in an result in a decrease in fat-soluble vitamin concentrations. Fewer LDL-cholesterol–lowering effect in mildly hypercholester- lipoprotein particles may, therefore, be available to carry caro- olemic subjects. Moreover, an absolute decrease in the plasma tenoids. Because it is common practice to express carotenoid concentration of oxLDL was equally observed in both the group consuming PS and the control group. Subjects did not report any 14. Stocker R, Keaney JF Jr. Role of oxidative modifications in atheroscle- adverse effects of PS consumption. In addition, we did not ob- rosis. Physiol Rev 2004;84:1381– 478.
serve alterations in adjusted plasma ␤-carotene concentrations; 15. Lusis AJ. Atherosclerosis. Nature 2000;407:233– 41.
16. Meisinger C, Baumert J, Khuseyinova N, Loewel H, Koenig W. Plasma equally, levels of oxidative stress as assessed by adjusted plasma oxidized low-density lipoprotein, a strong predictor for acute coronary concentrations of oxLDL were unchanged. Thus, the consump- heart disease events in apparently healthy, middle-aged men from the tion of very-low-fat PS-enriched FM may represent a useful general population. Circulation 2005;112:651–7.
additive therapeutic measure to the classic hypocholesterolemic 17. Devaraj S, Autret BC, Jialal I. Reduced-calorie orange juice beverage with plant sterols lowers C-reactive protein concentrations and improves diet of the American Heart Association in hypercholesterolemic the lipid profile in human volunteers. Am J Clin Nutr 2006;84:756 – 61.
patients at high cardiovascular disease risk.
18. Devaraj S, Jialal I, Vega-Lopez S. Plant sterol-fortified orange juice effectively lowers cholesterol levels in mildly hypercholesterolemic We kindly thank I Seksek, L Verseil, S Doat, and B Rumo for their healthy individuals. Arterioscler Thromb Vasc Biol 2004;24:e25– 8.
contribution to the present study. We also thank all the volunteers who 19. Noakes M, Clifton PM, Doornbos AM, Trautwein EA. Plant sterol ester-enriched milk and yoghurt effectively reduce serum cholesterol in The authors’ responsibilities were as follows—BH, YD, JF, MK, J-LS, modestly hypercholesterolemic subjects. Eur J Nutr 2005;44:214 –22.
and BV: collected data; and all authors: contributed to writing the manuscript.
20. Jauhiainen T, Salo P, Niittynen L, Poussa T, Korpela R. Effects of Statistical analyses were performed by OPTIMED. EB received honoraria low-fat hard cheese enriched with plant stanol esters on serum lipids and for presentations and grants for research studies from Unilever, Danone, and apolipoprotein B in mildly hypercholesterolaemic subjects. Eur J Clin Madaus. CN, FT, FL, and TL are employed by Danone. The other authors had 21. Algorta Pineda J, Chinchetru Ranedo MJ, Aguirre Anda J, Francisco Terreros S. [Hypocholesteremic effectiveness of a yogurt containingplant stanol esters]. Rev Clin Esp 2005;205:63– 6 (in Spanish).
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La rivolta del contadini di san salvatore monferrato - 14-25 ottobre 1898

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