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The Baseline Serum Lipoprotein Profile Is Related to Plant Stanol Induced Changes in Serum Lipoprotein Cholesterol and Triacylglycerol Concentrations

Department of Human Biology (E.N., J.P., R.P.M.)
Department of Statistics (A.D.M.K.), Maastricht University, Maastricht, THE NETHERLANDS

Address reprint requests to: R.P. Mensink, PhD, Department of Human Biology, Maastricht University, PO Box 616, 6200 MD, Maastricht, THE NETHERLANDS. E-mail: R.Mensink{at}HB.unimaas.nl

	ABSTRACT

TOP FOOTNOTES ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS REFERENCES

 
Objective: Baseline characteristics of subjects might be related to the effect of plant stanols on the serum lipoprotein profile. The aim of the study was to examine effects of subjects’ baseline characteristics (baseline serum concentrations of lipids and lipoproteins at the start of the study, lathosterol, campesterol and sitosterol; gender, age, BMI, smoking, use of oral contraceptives and menopause) on the effects of plant stanol esters on the serum lipoprotein profile.

Methods: We used data of five studies performed at our Department. A random intercept model was used for statistical analysis, using serum lipid and lipoprotein concentrations after plant stanol ester consumption, as dependent variables.

Results: After plant stanol ester consumption, higher baseline serum concentrations of total and LDL cholesterol resulted in larger absolute decreases in their respective serum concentrations. For the ratio of total to HDL cholesterol and triacylglycerol, higher baseline serum levels resulted in larger absolute and relative decreases in their serum levels. HDL cholesterol concentrations increased in subjects with low baseline concentrations and decreased in those with high baseline concentrations. Effects however were small. No relationships were observed with baseline serum cholesterol-standardized lathosterol and campesterol concentrations, although LDL cholesterol concentrations tended to decrease more at higher baseline sitosterol concentrations. No effects of other baseline characteristics were found.

Conclusions: People with an unfavorable serum lipid and lipoprotein profile benefit even more of plant stanols than people with a more favorable profile.

Key words: baseline subject characteristics, serum concentrations of plant sterols, plant stanols, LDL cholesterol, triacylglycerol

	INTRODUCTION

TOP FOOTNOTES ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS REFERENCES

 
A recent meta-analysis, based on mean reductions in serum LDL levels obtained in selected clinical studies with plant sterols and stanols, showed that a daily consumption of 2-2.5 g of plant sterols and stanols will lower serum concentrations of LDL cholesterol on average by 8.9% [1]. Between studies, however, reductions varied from 4% to 19% [2–14]. These differences might - at least partly - be explained by differences in baseline characteristics of the subjects. Indeed, a positive relationship between baseline and decreases in serum LDL cholesterol concentrations has been reported in one study [15], but this could not be confirmed in other studies [13,16,17].

Recently, however, we also found that consumption of margarines enriched with a mixture of plant sterols and stanols hardly changed serum LDL cholesterol in subjects with baseline LDL cholesterol concentrations 2.26 mmol/L, while it decreased serum concentrations of LDL cholesterol by approximately 0.35 mmol/L in subjects with baseline serum LDL cholesterol concentrations 3.36 mmol/L [18]. Although these differences in effects did not reach statistical significance, it provides evidence that the serum LDL cholesterol lowering effects of plant stanols may depend on baseline serum LDL cholesterol concentrations. Furthermore, it has been suggested that dietary plant stanols are especially of benefit for people with a high intestinal cholesterol absorption and a low endogenous cholesterol synthesis. Thus, baseline serum concentrations of markers of cholesterol absorption (campesterol and sitosterol) and cholesterol synthesis (lathosterol) may also predict the LDL cholesterol-lowering effect of plant stanols [19]. Gender however may not be an important determinant to explain differences in response between studies. In most studies, effects on the serum lipoprotein profile were similar in men and women [5,20,21], although Mussner et al. have suggested that plant sterol esters decreased LDL cholesterol slightly more in men than in women [22].

Finally, decreases in serum concentrations of LDL cholesterol were larger in elderly than those in younger people [1,23]. In general however, the statistical power of many of the individual studies was too low to examine the effects of these subjects’ baseline characteristics on the effects of plant stanols on the serum lipid and lipoprotein profile. To address these possible relationships more systematically, we decided to carry out a meta-analysis using the individual data from five studies performed at our Department [3,18,24–26]. Furthermore, effects of BMI, smoking, use of oral contraceptives and menopause on plant stanol induced changes in serum lipids and lipoproteins were evaluated.

	MATERIALS AND METHODS

TOP FOOTNOTES ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS REFERENCES

 
Characteristics of the Studies
Between 1997 and 2000 four randomized placebo-controlled trials on the effects of plant stanol esters on serum lipids and lipoproteins have been carried out at our Department [3,24–26]. In addition, one study was performed to examine the effects of two different mixtures of plant stanols and sterols on the serum concentrations of plant sterols. In that study, serum lipids were also measured [18]. For convenience however all diets are referred to as "enriched with plant stanols". In all studies plant stanols and sterols were esterified with rapeseed oil fatty acids. Characteristics of the studies are given in Table 1 and Table 2. Three studies had a parallel design [24–26] and two studies had a cross-over design [3,18]. Targeted daily intakes of plant stanols were 2 to 4 gram and duration of the treatments 3 to 8 weeks. In one study, plant stanols were incorporated into margarines and shortenings [3], in three studies into margarines [18,24,26] and in one study into a low fat yogurt [25]. In total, 301 subjects participated in these five studies, 104 men and 197 women. Of these subjects 28 people participated in two, 2 in three and 4 in four of the studies. Subjects had no hypertension, no presence of glucosuria, no use of medication or a diet known to affect serum lipids and lipoproteins, no abuse of drugs or alcohol, and no history of coronary heart disease. Further, all subjects were weight stable, had not participated in another biochemical trial or donated blood within the previous 30 days, were not pregnant or breast-feeding and did not use food products enriched with plant sterols or stanols. Average BMI was 23 to 25 kg/m² in all studies, 26 women were post-menopausal and 97 women used oral contraceptives. Individual data of smoking habits were not available for one trial [3]. In the other trials, 44 subjects were smokers [18,24–26]. During the studies, subjects did not change their habitual diet, level of physical exercise, smoking habits or use of alcohol or oral contraceptives during the studies. The study protocols were approved by the medical ethical committee of Maastricht University. All subjects gave written informed consent before the start of the trials.

Analyses of lipids and lipoproteins were performed in all studies, analyses of lathosterol, campesterol and sitosterol in three of the five studies [18,24,25,27]. All analyses were done in serum obtained by centrifuging a serum tube for 15 [3,25] or 30 minutes [24,26,28] at 2000 x g at 4 °C, at least 1 hour after venipuncture. All samples were stored at –80 °C until analyses of lipids and lipoproteins and non-cholesterol sterols. Samples of one subject were always analyzed in one run. Serum concentrations of total cholesterol, HDL cholesterol and triacylglycerol were determined as described [24]. Serum concentrations of LDL cholesterol were calculated using the Friedewald equation [29]. For analyses of non-cholesterol sterols, sera from two blood samples at the end of the run-in periods and at the end of the intervention periods for parallel trials and at the end of each dietary period for the cross-over trial were pooled. Analyses were performed as described elsewhere [27].

Statistics
A random intercept model was used for statistical analysis, using serum concentrations of total cholesterol, LDL cholesterol, HDL cholesterol, triacylglycerol and the ratio of total to HDL cholesterol as dependent variables. For this, the data were rearranged so that for cross-over trials the end-of-period measurements and for parallel trials the end-of-run-in and end-of-intervention values were on separate lines. Subject was included as random factor in order to obtain estimates of plant stanol effects based on within-subject differences. A fixed factor for measurement number was included to correct for possible time-trend effects. For parallel trials, this number was 1 or 2, indicating respectively serum lipoprotein concentrations at the end of the run-in period and at the end of the intervention period. For cross-over trials, measurement numbers were 1, 2 and 3 for serum lipoprotein concentrations at the end of the three dietary periods. In addition, a fixed factor for trial was included as well as the interaction between trial and measurement number to account for possible different period effects per trial. To answer the questions whether baseline subject characteristics are related to the cholesterol-lowering effects of plant stanols, the amount of daily plant stanol intake was included into the model as covariate, together with an interaction term for the variable of interest, for example the serum total cholesterol concentrations at baseline.

A statistically significant interaction term indicates that effects of plant stanol intake are related to baseline concentrations of total cholesterol. In the same way, effects of other variables (baseline serum concentrations of LDL cholesterol, HDL cholesterol, triacylglycerol and the ratio of total to HDL cholesterol; cholesterol-standardized concentrations of lathosterol, campesterol, sitosterol and the ratios of lathosterol to campesterol and of lathosterol to sitosterol at the end of the run-in period for parallel trials and at the end of the control period for the cross-over trial (also referred to as baseline concentrations); gender, age, BMI, smoking, use of oral contraceptives and menopause) on the cholesterol lowering effects of plant stanols were tested. Unless otherwise indicated, all models included the interaction term between plant stanol intake and baseline serum concentration of the lipid variable of interest. A p-value of <0.05 was considered statistically significant. Analyses were performed using SPSS 11.5 (SPSS, Chicago, IL, USA) using the mixed model option within the General Linear Model procedure.

	RESULTS

TOP FOOTNOTES ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS REFERENCES

 
Effect of Baseline Serum Lipids and Lipoproteins
The absolute decrease in serum total cholesterol concentrations after consumption of plant stanols was related to baseline serum concentrations of total cholesterol (p = 0.002 for the interaction term (Table 3). At a baseline serum total cholesterol concentration of 4.00 mmol/L and a daily plant stanol intake of 2 g, the expected change in serum concentration of total cholesterol is calculated as: (0.017 x 2) –(0.025 (4.0 x 2)) = –0.17 mmol/L or 4.2% (95% confidence interval (CI): –0.22 to –0.12 mmol/L or –5.5 to –3.0%). At a similar intake, the expected decrease at a baseline serum concentration of 6.00 mmol/L is 0.27 mmol/L or 4.4% (95% CI: –0.32 to –0.22 mmol/L or –5.3 to –3.7%) and at a baseline serum concentration of 8.00 mmol/L the expected decrease is 0.37 mmol/L or 4.6% (95% CI: –0.47 to –0.27 mmol/L or –5.9 to –3.4%). This indicates that baseline serum concentrations of total cholesterol are related to the absolute, but hardly to the relative reductions in serum total cholesterol concentrations (Fig. 1). Baseline serum concentrations of LDL cholesterol were also only related to absolute decreases in serum LDL cholesterol (p < 0.001 for the interaction term, Fig. 2, 95% CI for the changes at a baseline LDL cholesterol concentration of 3.00 mmol/L: – 0.24 to –0.17 mmol/L or –8.0 to –5.7% per 2 g of stanol intake; 95% CI at a baseline LDL cholesterol concentration of 4.00 mmol/L: –0.32 to –0.22 mmol/L or –8.0 to –5.5% per 2 g of stanol intake; 95% CI at a baseline LDL cholesterol concentration of 5.00 mmol/L: –0.41 to –0.27 mmol/L or –8.2 to –5.4% per 2 g of stanol intake). Effects on HDL cholesterol did also depend on baseline concentrations (p = 0.031 for the interaction term, Fig. 3). Estimated changes were however small. At a baseline HDL cholesterol concentration of 1.00 mmol/L, the estimated increase in HDL cholesterol was 0.01 mmol/L or 1.4%. When the baseline concentration was 1.50 mmol/L, the change was 0.00 mmol/L and at a baseline concentration of 2.00 mmol/L –0.02 mmol/L or –0.9%.

View larger version (28K): [in this window] [in a new window]   Fig. 1. Predicted change in serum concentrations of total cholesterol at different baseline concentrations and at different amounts of daily plant stanol intake.

View larger version (28K): [in this window] [in a new window]   Fig. 2. Predicted change in serum concentrations of LDL cholesterol at different baseline concentrations and at different amounts of daily plant stanol intake.

View larger version (20K): [in this window] [in a new window]   Fig. 3. Predicted change in serum concentrations of HDL cholesterol at different baseline concentrations and at different amounts of daily plant stanol intake. At a baseline concentration of 1.5 mmol/L the predicted changes were close to zero.

View larger version (26K): [in this window] [in a new window]   Fig. 4. Predicted change in the ratio of total cholesterol to HDL cholesterol at different baseline concentrations and at different amounts of daily plant stanol intake.

View larger version (25K): [in this window] [in a new window]   Fig. 5. Predicted change in serum concentrations of triacylglycerol at different baseline concentrations and at different amounts of daily plant stanol intake.

Effects of Baseline Serum Lathosterol, Campesterol and Sitosterol
Baseline serum concentrations of cholesterol-standardized lathosterol, campesterol and sitosterol of the three studies used in this meta-analysis are presented in Table 4. Interaction terms for baseline serum concentrations of cholesterol-standardized lathosterol, campesterol, the ratio of lathosterol to campesterol, the ratio of lathosterol to sitosterol and the ratio of lathosterol to plant sterols (campesterol plus sitosterol) x plant stanol intake were not significant, indicating that baseline non-cholesterol sterols were not related to decreases in serum concentrations of lipids and lipoproteins. The interaction term for baseline serum concentrations of sitosterol x plant stanol intake nearly reached statistical significance for LDL cholesterol (p = 0.062, Table 5). The results suggest that at higher baseline sitosterol concentrations, decreases in serum concentrations of LDL cholesterol were more pronounced. Baseline serum concentrations of sitosterol did not affect changes in total cholesterol, HDL cholesterol, triacylglycerol and the ratio of total to HDL cholesterol. Effects on serum lipids and lipoproteins of these three studies only were comparable to those of all five studies.

	DISCUSSION

 
Large variations have been reported between studies and between subjects on the effects of consumption of plant sterols and stanols on LDL cholesterol concentrations [1]. These variations might not only be due to differences in experimental designs, but also to differences in baseline characteristics of the subjects. Single trials, however, normally lack the statistical power to identify subjects’ characteristics related to changes in serum lipids and lipoproteins. We therefore decided to carry out a meta-analysis with individual data of five studies performed at our Department. In this way, variations in responses due to different study centers were excluded. We found that absolute but not relative decreases in serum LDL cholesterol concentrations were related to their serum concentrations at the start of the study. Predicted reductions in serum LDL cholesterol at different doses of plant stanol intake were however slightly lower than those calculated from 56 trial arms with plant sterols and stanols [1]. In our model, at a baseline LDL cholesterol concentration of 3.55 mmol/L (the mean LDL cholesterol concentration in the placebo groups from the meta-analysis of Katan et al. [1]), the predicted decreases at daily doses of 1.7, 2.2 and 3 g of stanols were 5.8%, 7.5% and 10.2%, while decreases were respectively 8.5%, 8.9% and 11.3% in the meta-analysis [1].

In the present study we found that after plant stanol ester consumption HDL cholesterol increased slightly in people with low baseline concentrations, but decreased marginally in subjects with high baseline HDL cholesterol concentrations. This effect was not related to gender. These findings were unexpected, because most studies have reported no effects of plant stanols or sterols on serum concentrations of HDL cholesterol. However, in subjects with familial hypercholesterolemia plant sterols increased serum HDL cholesterol. This increase was larger the lower the baseline HDL cholesterol concentrations [30]. An increase in serum concentrations of HDL cholesterol has also been reported in subjects with type 2 diabetes mellitus using a cross-over design [31]. Although HDL cholesterol concentrations in that study were not extremely low during the control period (1.13 mmol/L), it is known that subjects with type 2 diabetes in general have lower HDL cholesterol levels than healthy controls [32]. In our study predicted changes were small. For example, at a baseline HDL cholesterol of 2.00 mmol/L and a daily plant stanol intake of 2 g, HDL cholesterol concentrations are expected to decrease by only 0.02 mmol/L. This will not increase cardiovascular risk, as at the same time LDL cholesterol will decrease substantially. Also, only a low proportion of the population will have baseline HDL cholesterol > 2.00 mmol/L and plant stanol enriched food products are not designed for this population. Both absolute and relative decreases in the ratio of total to HDL cholesterol, which is considered superior to total or lipoprotein cholesterol concentrations to estimate cardiovascular risk [33], were positively related to baseline concentrations. This suggests that especially people with an unfavorable ratio of total to HDL cholesterol benefit from plant stanol ester consumption.

Both absolute and relative decreases in serum triacylglycerol concentrations were positively related to those at baseline. As triacylglycerol, which is positively associated with the risk of coronary heart disease [34,35], is mainly transported by VLDL, it can be suggested that VLDL metabolism changes after plant stanol consumption. Gylling et al. indeed observed decreased serum concentrations of VLDL cholesterol during stanol consumption, which might indicate that VLDL synthesis is reduced. However, serum concentrations of triacylglycerol remained unchanged [31]. On the other hand, in one study with 18 subjects, plant sterols lowered triacylglycerol concentrations [30]. The power of single studies is usually not sufficient to detect changes on serum triacylglycerol concentrations. Our model estimates a decrease of only 0.04 mmol/L at baseline concentrations of triacylglycerol of 1.5 mmol/L and a daily plant stanol intake of 2 g. To pick up this difference, about 450 subjects are needed in a cross-over trial and 1700 in a study with a parallel design with a statistical power of 80%.

In people with high cholesterol absorption and low cholesterol synthesis, indicated by high baseline plant sterol concentrations and low lathosterol concentrations, LDL cholesterol reduction is more pronounced than in people with low cholesterol absorption and high cholesterol synthesis [15,19,36,37]. To analyze if this was also present in our population, we included serum concentrations of lathosterol, campesterol and sitosterol and the ratio of serum concentrations of lathosterol to the plant sterols (campesterol plus sitosterol) in our model. However, we only observed a tendency for an increased reduction in serum concentrations of LDL cholesterol at increasing baseline sitosterol concentrations.

Effects of age were explained by baseline LDL cholesterol concentrations, which has been suggested previously [1]. We further observed that plant stanol esters may reduce LDL cholesterol slightly more in men than in women. This however does not mean that men will benefit more than women in terms of coronary heart disease risk. From our model and the data provided by Sacks and Katan [38], we can calculate the predicted reduction in coronary heart disease risk for men and women based on changes in serum lipids. For example, at a daily plant stanol intake of 2 g and baseline concentrations of LDL cholesterol of 4 mmol/L, HDL cholesterol of 1 mmol/L and triacylglycerol of 2 mmol/L, the expected decrease in coronary heart disease risk would be 10% for men and 12% for women. Another meta-analysis also reported differences between men and women in diet-induced LDL cholesterol responses [28]. In that study it was found that men would benefit more from decreasing saturated fatty acid intake than women for which there was no explanation.

To summarize, our meta-analysis showed that decreases in LDL cholesterol and the ratio of total to HDL cholesterol are most pronounced in subjects with the highest baseline levels of these cardiovascular risk markers. In addition, plant stands may decrease serum concentrations of triacylglycerol especially in people with high serum concentrations of triacylglycerol. Other subjects’ characteristics did not contribute substantially to the predicted changes, thereby underlining that functional foods enriched with plant stanol esters are of benefit for most people with an unfavorable lipoprotein profile.

	FOOTNOTES

TOP FOOTNOTES ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS REFERENCES

 
Dr. Naumann is currently at HAN University, Department of Nutrition and Dietetics, Nijmegen, The Netherlands.

Received March 20, 2006. Accepted November 21, 2006.

	REFERENCES

TOP FOOTNOTES ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS REFERENCES

 

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