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Journal of the American College of Nutrition, Vol. 25, No. 1, 41-48 (2006)
Published by the American College of Nutrition

Phytosterols/Stanols Lower Cholesterol Concentrations in Familial Hypercholesterolemic Subjects: A Systematic Review with Meta-Analysis

Kgomotso G. Moruisi, RD, Welma Oosthuizen, PhD and Anna M. Opperman, PhD

School of Physiology, Nutrition and Consumer Science, North-West University, Potchefstroom, SOUTH AFRICA

Address correspondence to: Dr Welma Oosthuizen, School of Physiology, Nutrition and Consumer Science, North-West University, Private Bag X6001 (Internal box 594), Potchefstroom, 2520, SOUTH AFRICA. E-mail: VGEWO{at}puk.ac.za


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Background: To-date, reviews regarding the cholesterol lowering capacity of phytosterols/stanols have focused on normo- and hypercholesterolemic (HC) subjects. Familial hypercholestrolemia (FH) is characterized by very high low-density lipoprotein cholesterol (LDL-C) concentrations and is considered a world public health problem due to the high incidence of premature coronary heart disease (CHD) in these patients.

Objective: To conduct a systematic review that investigates the efficacy of phytosterols/stanols in lowering total cholesterol (TC) and LDL-C concentrations in FH subjects.

Design: Randomized controlled intervention trials with the primary objective to investigate the effects of phytosterols/stanols on lipid concentrations in FH subjects were identified through selected international journal databases and reference lists of relevant publications. Two researchers extracted data from each identified trial and only trials of sufficient quality (e.g. controlled, randomized, double-blind, good compliance, sufficient statistical power) were included in the review. The main outcome measures were differences between treatment and control groups for LDL-C, TC, high-density lipoprotein cholesterol (HDL-C) and triacylglycerol (TG).

Results: Six out of 13 studies were of sufficient quality. Two were excluded from the meta-analysis because the sterols were administered in the granulate form at very high dosages (12 g/day and 24 g/day) compared to the other studies that used fat spreads as vehicle with dosages ranging from 1.6–2.8 g/day. The subjects were heterozygous, aged 2–69 years with baseline TC and LDL-C concentrations of ±7 mmol/L and ±5.4 mmol/L, respectively. The duration of the studies ranged from 4 weeks to 3 months. Fat spreads enriched with 2.3 ± 0.5 g phytosterols/stanols per day significantly reduced TC from 7 to 11% with a mean decrease of 0.65 mmol/L [95% CI –0.88, –0.42 mmol/L], p < 0.00001 and LDL-C from 10–15% with a mean decrease of 0.64 mmol/L [95% CI –0.86, –0.43 mmol/L], p < 0.00001 in 6.5 ± 1.9 weeks compared to control treatment, without any adverse effects. TG and HDL-C concentrations were not affected.

Conclusion: Phytosterols/stanols may offer an effective adjunct to the cholesterol lowering treatment strategy of FH patients.

Key words: phytosterols, stanols, familial hypercholesterolemia, heterozygous, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Familial hypercholesterolemia (FH) is an inherited autosomal dominant disorder of the lipoprotein metabolism caused by mutations on the low density lipoprotein (LDL) receptor gene. FH is characterized by very high concentrations of LDL-cholesterol (LDL-C), family history of hypercholesterolemia (HC), tendon xanthomas, xanthelasma or corneal arcus, and personal and family history of premature coronary heart disease (CHD) [1,2]. FH is one of the most frequent monogenic hereditary disorders in the general population [2]. In most countries the frequency of heterozygous FH is approximately 1 in 500 individuals [2,3]. However, in the South African Caucasian Afrikaans speaking population the prevalence is 1 in 72 [4], due to a founder effect in this population [5].

It is established that diet therapy is the cornerstone in lowering total cholesterol (TC) and LDL-C concentrations and in reducing the risk of cardiovascular disease (CVD). Treatment of FH in adults generally involves a cholesterol-lowering diet and statin use. Currently, the therapeutic options for treating elevated cholesterol levels in FH children are limited and generally include cholesterol-lowering diet and if necessary, bile acid sequestrants. The onset of drug treatment in childhood has, however, potential difficulties including long-term safety, poor compliance and cost effectiveness [2].

The incorporation of plant sterols/stanols in the diet of heterozygous FH patients may be a useful tool for LDL-C lowering [2]. In a recent review of 19 randomized controlled trials, it was concluded that phytosterols/stanols incorporated in different food vehicles such as margarine/fat spreads, butter, salad dressings, mayonnaise, chocolate, low fat yogurt, bakery products and ground beef significantly reduced LDL-C concentrations between 8% and 15% at a dose of 1.5–3 g/day [6]. During the past five years many reviews, most of them narrative reviews, have been published regarding the cholesterol lowering effect of phytosterols/stanols [6–14]. These reviews focused mainly on non-FH subjects and often excluded the FH subjects. In addition, the NCEP/ATP III has recommended 2 g/day of plant stanols/sterols as an effective dose for enhancing LDL-C reduction [15]. No dietary recommendations for the intake of plant sterols/stanols by adults and children with FH have, however, been established. Our objective is therefore, to conduct a systematic review with meta-analysis to investigate the effects of plant sterols/stanols in adults and children with FH.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Identification of Trials
Studies were included in the systematic review if they had a randomized controlled study design and the primary objective was to investigate the effects of phytosterols/stanols on TC, and LDL-C concentrations in children or adults with FH.

The literature search included studies published between 1976 and August 2004. The studies were identified through international journal databases such as Science Direct, Medline, Health Source and Academic Search Premier. The search was done using the key words (plant sterol* or phytosterol*) and (cholesterol* or lipid*) and (familial hypercholesterol*). The trial register of Current Controlled Trials [16] was also searched, and no studies could be found that met the set inclusion criteria. A further search was done by scanning the reference lists of original and review publications. Although the search was not limited to English, all the identified studies were in English. The study selection process that was followed is illustrated in Fig. 1.


Figure 1
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  		Fig. 1. Study Selection Process

 
Extraction of Data and Quality Assessment
Two independent researchers (KGM and WO) extracted the relevant data from the publications by using an agreed standardized form. Furthermore, the two researchers independently assessed the quality of the research methodology by using a list of quality criteria items extracted from The Delphi List [17] in Table 1. The following quality scores were then allocated to each trial:
  1. if all of the above criteria items were present
  2. if controlled and two criteria items were missing
  3. if not controlled or three or more criteria items are missing.


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  		Table 1. Quality Criteria List for Randomized Controlled Trials1

 
Only the studies with a quality score of 1 or 2 were included in the systematic review.

Data Analysis
A trained researcher in meta-analysis (A.M.O.) was involved. The Cochrane Collaboration Review Manager 4.2.5 software package (Oxford, England) was used to perform the meta-analysis. For each trial, standard deviation of treatment for the outcome measures (TC, LDL-C, HDL-C and TG) were estimated using methods described by Follman et al. [18]. Net changes in TC, LDL-C, HDL-C and TG are expressed in mmol/L. Variables expressed in mg/dL were converted to mmol/L by using the following conversion factors: for TC, LDL-C and HDL-C the value was divided by 38.7, and for TG the value was divided by 88.2. The meta-analysis for TC, LDL-C and HDL-C was performed on four trials [19–22]. The reasons for excluding two trials [23,24] are discussed in the following section. For TG, the meta-analysis was only performed on two trials [21,22] as the data in the other two trials [19,20] were presented as geometric mean (range) and median (range) instead of mean ± SD and mean ± SEM. The meta-analysis was carried out using a ‘random effects’ statistical model, and the robustness of the results was examined by using both the ‘fixed effect’ and ‘random effects’ statistical models. The differences between trials included in the meta-analysis were checked for heterogeneity by visual inspection of the forest plots and by using I2.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
ACKNOWLEDGMENTS
 REFERENCES
 
The literature search yielded 13 studies of which six trials qualified to be used in the systematic review and four in the meta-analysis (Fig. 1). All the studies were done on heterozygous subjects, aged 2 to 69 years and the duration of the trials ranged from 4 weeks to 3 months. Mean baseline total cholesterol and LDL-C concentrations were ±7.0 mmol/L and ±5.4 mmol/L, respectively. The trials were carried out under free-living conditions and used plant sterols or plant stanols. In the late 1970s sterols were administered in granulate form and much higher dosages were used, 12 g/day [23] and 24 g/day [24]. In the other studies [19–22], fat spreads were used as vehicle for the sterols/stanols and the dosages ranged from 1.6 to 2.8 g sterols/stanols per day (Table 2).


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  		Table 2. Hypocholesterolemic Effects of Phytosterol/Stanol Treatment on Lipid Concentrations in Heterozygous Familial Hypercholesterolemic Subjects

 
The main reasons for the exclusion of seven studies in the systematic review were that two reported inappropriate outcome measures and five had more than three quality criteria items missing, for example, studies were not double-blinded, not randomized, not controlled, sample size not justified, adherence to treatment not reported and carry over effect not taken care of [25–29].

The results of the two trials [23,24] that used very high dosages administered in granulate form were excluded from the meta-analysis since several studies have found that high dietary intakes of plant sterols are not necessary as they may lower carotenoid concentrations [30–34] and elevate plasma plant sterol levels with no additional cholesterol lowering effect [30]. Furthermore, NCEP/ATP III has established that 2 g/day of phytosterols/stanols is an effective dose to reduce LDL-C in mild and moderate HC subjects [15].

The results of the systematic review are summarized in Table 2 and Fig. 2. The greatest significant LDL-C (14–15%) and TC (11%) reductions were seen in studies on children with the highest dosages of 2.3 g/day plant sterol (19) and 2.8 g/day plant stanol [22] enriched spreads. Intake of 1.6 g/day plant sterol-enriched spread by children resulted in reductions of 10.2% in LDL-C and 7.4% in TC concentrations. In the adult group, 2.5 g/day plant sterol-enriched spread [20] caused a reduction of 10% in LDL-C and 8% in TC concentrations (Table 2 and Fig. 2). In the study of Schlierf et al. [23] 12 g/day of ß-sitosterol reduced HDL-C markedly by 15%, whereas none of the other studies showed this adverse effect. TG concentrations were not affected.


Figure 2
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  		Fig. 2. Effect of phytosterol/stanol versus control on TC and LDL-C concentrations in familial hypercholesterolemic subjects. LDL-C = low-density lipoprotein cholesterol, TC = total cholesterol.

 
Both statistical methods used in the meta-analysis namely the ‘fixed effect’ and the ‘random effects’ statistical models produced similar results, therefore, the results presented are for the ‘random effects’ model.

Results of the meta-analysis on TC and LDL-C are presented in forest plots (Figs. 3 and 4, respectively). The forest plot presents the individual study effects with their confidence intervals as horizontal lines, the shorter the line, the more significant the results are. The box in the middle of the horizontal line represents the mean effect, the size of the box represent the weight each study contributed to the analysis (presented as weighted mean difference). The vertical line at zero represents no effect. The diamond shape at the bottom of each graph represents mean overall difference between treatment and control, if it does not touch the vertical line it indicates that the overall effect is statistically significant.


Figure 3
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  		Fig. 3. Effects of phytosterols/stanols on total cholesterol of familial hypercholesterolemic subjects. CI = confidence interval, N = sample size, SD = standard deviation, WMD = weighted mean difference.

 

Figure 4
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  		Fig. 4. Effects of phytosterols/stanols on low-density lipoprotein cholesterol of familial hypercholesterolemic subjects. CI = confidence interval, N = sample size, SD = standard deviation, WMD = weighted mean difference.

 
Figs. 3 and 4 summarize the treatment effect of 2.3 ± 0.5 g phytosterols/stanols/day on TC and LDL-C of 124 FH subjects for 6.5 ± 1.9 weeks of intervention. Total cholesterol was significantly reduced by 0.65 mmol/L [95% CI –0.88, –0.42 mmol/L], p < 0.00001 and LDL-C by 0.64 mmol/L [95% CI –0.86, –0.43 mmol/L], p < 0.00001. These results were statistically homogeneous as reflected by an I2 of 0% meaning that the studies in this meta-analysis presented similar results. There were no effects seen on HDL-C and TG concentrations (data not shown). The I2 values for HDL-C and TG were 0% and 46.1% respectively.


   DISCUSSION
 
All effort was made to find all the published studies that investigated the effect of phytosterols/stanols on lipid concentrations in FH subjects. In this regard, the search strategy included both computerized and manual searching methods and several international databases were searched from the mid-1970s. Possible bias was further minimized by not limiting the search to English language publications and all the identified published studies were in English. Publication and citation bias can, however, not be excluded. Furthermore, the studies included in the meta-analysis were heterogenous as indicated by an I2 value of 0% for TC, LDL-C and HDL-C. The I2 value for TG was, however 46.1%, reflecting heterogeneity between studies. This may be ascribed to the fact that only two studies were included in the meta-analysis on TG due to different reporting of results. The effects on TG concentrations in these two studies were in the same direction compared to the other studies.

The results of this systematic review are in accordance with results from studies on non-FH subjects [6]. Quílez and colleagues [6] concluded from their review of 19 randomized controlled trials that 1.5–3 g of phytosterols/stanols per day led to 8–15% reductions in LDL-C in normocholesterolemic, mildly HC and HC subjects with no effect on HDL-C and TG. In this systematic review and meta-analysis on heterozygous FH subjects, LDL-C concentrations were decreased from 10–15% with a mean decrease of 0.64 [–0.86, –0.43] mmol/L with intakes ranging from 1.6–2.8 g (2.3 ± 0.5 g) phytosterols/stanols per day which is in line with the 2g plant sterols/stanols per day recommended by the NCEP/ATP III [15]. Almost all heterozygous FH patients need to reduce their LDL-C concentrations by over 40% to reach target levels [2]. Therefore, phytosterol/stanol intake alone will not be sufficient in FH patients and will have to take place in conjunction with a healthy lifestyle, the use of a combination of other cholesterol lowering foods (portfolio diet) [35] and/or lipid lowering drug treatment. The portfolio diet (combination of plant sterols, soy proteins, viscous fiber and nuts) has been shown in hyperlipidemic subjects to have the same potency than statin treatment in achieving lipid goals for primary prevention [35]. Nevertheless, phytosterol/stanol intake will contribute to a reduced risk of CHD in FH patients. It was estimated from a meta-analysis of 58 randomized trials of cholesterol lowering by any means that for an LDL-C reduction of 1.0 mmol/L the risk of ischaemic heart disease (IHD) events was reduced by 11% in the first year of treatment, 24% in the second year, 33% in years three to five and by 36% thereafter. After results of the first two years were excluded LDL-C reductions of 0.5 mmol/L, 1.0 mmol/L and 1.6 mmol/L reduced IHD events by 20%, 31% and 51%, respectively [36]. A meta-analysis of 14 randomized trials of statins showed that the five year incidence of major coronary events, coronary revascularization and stroke was reduced by one fifth per 1.0 mmol/L reduction in LDL-C [37]. Although these estimates were based on general populations, most heterozygous FH patients should benefit as much as other high-risk groups from LDL-C reduction [2].

The decrease reported in HDL-C concentrations with intakes of 12 g/d ß-sitosterols in the granulate form, may probably be explained by chance or other factors since HDL-C concentrations is not affected by intake of phytosterol in clinical trials [6].

The studies included in the meta-analysis reported either no or only minor side effects. Gastrointestinal side effects (flatulence, abdominal discomfort, diarrhea and constipation) [20] and reduced lipid-adjusted serum lycopene concentrations [21] were reported. No gastrointestinal side effects were, however, reported in a long-term (1 yr) study of safety with consumption of plant sterol ester-enriched spread [38]. A reduction in carotenoid concentrations may be prevented if the intake of fruits and vegetables are increased during the consumption of plant sterol/stanol enriched spreads [39,40]. Therefore, children and adults with FH can be advised to when plant sterol-enriched food products are included in their hypocholesterolemic diets that care should be taken that the diets contain sufficient amounts of fruits and vegetables, especially carotenoid-rich vegetables or fruits.

The effects on LDL-C concentrations with intakes of sterols, sterol esters or stanol (saturated sterols) esters were similar. The following mean LDL-C reductions were reported: sterols, 10% and 14% [19,20]; sterol esters, 10% [21] and stanol esters, 15% [22]. Other randomized placebo controlled trials that compared plant sterol and stanol esters on a head-to-head basis also reported similar LDL-C lowering efficacy [41,42]. However, O’Neill et al [43] recently showed in a randomized trial on healthy subjects and patients with FH receiving statins that over a longer term (2 months) the LDL-C lowering efficacy of plant sterol esters was attenuated compared to plant stanol esters that maintained the LDL-C lowering effect. The authors concluded that plant stanol esters may be preferable for the long-term management of hypercholesterolemia.

The phytosterols/stanols in the different studies were administered in the form of either granulate or fat spreads. Compliance to the phytosterol/stanol-enriched fat spreads was very good, ranging from 92% to 97% for the three studies where compliance rate was reported [19–21]. The fact that these plant sterol-enriched fat spreads did not taste differently from ordinary fat spreads, unlike when given in the granulate form, probably contributed to the good reported compliance. Different types of vehicles, including salad dressings, mayonnaise, chocolate, low fat yogurt, bakery products and ground beef have been proven to be effective in normocholesterolemic, mildly HC and HC subjects [6]. Although no studies have been conducted on FH subjects using these vehicles it can be speculated that the effects will be the same as long as the vehicle enables the phytosterols/stanols to be solubilized in the fat phase of the food and to be incorporated into the micelles [6] and fits into the cholesterol lowering diet. A greater variety of sterol/stanol enriched foods may be of benefit to the FH population, especially those who do not use fat spreads.

In conclusion, fat spreads enriched with 2.3g phytosterols/stanols/day, significantly reduced TC and LDL-C concentrations in FH subjects by 0.65 [–0.88, –0.42] mmol/L and 0.64 [–0.86, –0.43] mmol/L, respectively in 6.5 weeks without causing any adverse side effects. Compared to the literature on non-FH subjects, phytosterol/stanol treatment were as effective in FH as in non-FH subjects. Phytosterols/stanols may be an effective and useful tool to contribute to cholesterol lowering in adult FH subjects. In children, it offers an acceptable and effective hypocholesterolemic treatment especially since adherence to lipid lowering drugs and diet may be insufficient.


   ACKNOWLEDGMENTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 ACKNOWLEDGMENTS
REFERENCES
 
We declare that we have no conflict of interest. Contributions of authors are as follows. K.G.M.: Main author, responsible or involved in all aspects of the study namely literature search, extraction of data, quality assessment of studies, meta-analysis, interpretation and discussion of results. W.O.: Co-author of manuscript, extraction of data, quality assessment of studies interpretation and discussion of results. A.M.O.: All aspects related to the meta-analysis.

Received March 31, 2005. Accepted December 21, 2005.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 ACKNOWLEDGMENTS
 REFERENCES
 

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