Plant Sterols and Stanols in the Treatment of Hypercholesterolemia
January 2000; Volume 3: 6-10
By Philippe O. Szapary, MD and Michael D. Cirigliano, MD, FACP
Cardiovascular disease (cvd) is the number one cause of death in industrialized nations, and within CVD, coronary artery disease (CAD) is still the leading cause of death, especially in men over 45 years and women over 65 years old. Serum cholesterol is a potent marker for the development of clinical CAD: A 10% reduction in cholesterol reduces the risk of a coronary event by 18%, and the risk of CAD death by 10%.1 The most recent National Cholesterol Education Program (NCEP) estimates that 30% of American adults have elevated serum cholesterol levels that require non-pharmacologic intervention, while 7% merit cholesterol-reducing drugs.2 Naturally-occurring plant sterols (phytosterols) and their derivatives (stanols and stanol esters) represent a class of biologically active compounds that have been shown to reduce serum cholesterol. Many clinical trials have shown a reduction in low-density lipoprotein (LDL-C) levels by up to 14%.3 Based on current evidence, phytosterols and their derivatives are useful, non-pharmacologic adjunctive agents in reducing elevated serum cholesterol levels, especially in those who do not need to reduce their total calorie intake.
History
Since the 1950s, it has been recognized that adding the phytosterol ß-sitosterol to the diet of cholesterol-fed chickens and rabbits lowered their cholesterol levels.4 Since then, more than 100 reports describing the cholesterol-lowering efficacy of plant sterols and stanols in more than 18,000 human subjects have been published.4
Which of the following statements about plant sterols is/are true?
a. There are more than 44 naturally occurring plant sterols.
b. Sterols are found in pine trees.
c. Sterols are structurally similar to cholesterol.
d. Sterols can improve BPH symptoms.
e. All of the above.
Source and Identification
At least 44 sterols from seven different plant classes have been identified. The most abundant are ß-sitosterol and campesterol.5 Phytosterols are found in trees (especially pine), soybeans, corn, squash, vegetable oils, and grains. Currently, the largest source of commercial sterols comes from "tall oil," a byproduct of the paper pulping industry. The typical Western diet contains approximately 160-180 mg/d of phytosterols, compared to vegetarian diets, which contain approximately 370-400 mg/d of phytosterols.5
While initial studies used large doses of naturally-occurring plant sterols, more recent studies have focused on lower doses of processed sterols called stanols and their esters. Unlike sterols, stanols are virtually absent from typical diets. Both esterified sterols and stanols have been incorporated into fatty foods such as mayonnaise, margarine, and salad dressing. In general, these fatty foods contain < 1 g/serving of unsaturated trans fatty acids, which are associated with an increased risk of CAD. Processed food products containing sterol and stanol esters are often marketed in the United States and Europe as cholesterol-lowering functional foods.
Pharmacology
Structurally, phytosterols are very similar to cholesterol. They differ in their chemical structure only by the presence of an additional ethyl group (sitosterol) or methyl group (campesterol) at the C-24 position of the side chain.6 These phytosterols can then be saturated by hydrogenation to yield the 5 a-stanols such as sitostanol and campestanol. Hydrogenation produces primarily cis fatty acids, but a small amount of trans fatty acids is also formed (< 1.5% of the total fat per serving). Finally, both sterols and stanols can be esterified with fatty acids from vegetable oils (usually canola) to form sterol esters and stanol esters, which can then be more readily incorporated into foods.
Thus, there are two major classes of hypolipidemic compounds: sterols and stanols. The major difference between them are that sterols are found in nature and are systemically absorbed. Stanols on the other hand, because of hydrogenation, are not systemically absorbed and are not found in nature in substantial amounts. Most of the published research has been done with stanols.
Mechanism of Action
The primary mode of action by which sterols and stanols reduce serum cholesterol is by decreasing cholesterol absorption from the small intestine.7 Both these agents have a higher affinity than cholesterol for mixed bile salt micelles formed in the small bowel. By displacing cholesterol from these micelles, sterols and stanols decrease cholesterol absorption and subsequently, serum cholesterol as well.7
One recent study quantified this effect, showing that 3 g of sitostanol ester decreased both dietary and biliary cholesterol absorption by 44% and 37% respectively.8 This same study found that the increased fecal excretion of cholesterol was accompanied by a compensatory increase in cholesterol synthesis by 39%. Other studies have shown that patients with high intestinal cholesterol absorption and low endogenous cholesterol synthesis respond best to phytosterols.9 To date however, there are no readily available serum markers to distinguish patients whose hypercholesterolemia is secondary to enhanced absorption of intestinal cholesterol vs. increased synthesis of cholesterol.
The following statements about plant stanols are correct except:
a. stanols are absorbed by the GI tract.
b. stanols can lower LDL-C by 14%.
c. stanols are the active ingredient in Benecol® products.
d. stanols are effective in reducing serum cholesterol in diabetics.
e. stanols have a synergistic effect when used with statins.
Clinical Trials
Searching MEDLINE, PubMed, the Cochrane Collaboration database, and CINAHL, we identified more than 20 randomized, controlled trials (RCT) since 1976 evaluating the safety and efficacy of various sterols, stanols, and stanol esters in the treatment of hyperlipidemia. The majority of RCTs used plant stanol esters (PSE) incorporated into margarine. Of note, some of these studies dealt specifically with children, pre- and postmenopausal women, diabetics, patients with known CAD, and patients already taking HMG-CoA reductase inhibitors (i.e., statins).
The largest and longest trial was a double-blind RCT of 153 subjects with mild hypercholesterolemia defined as total cholesterol (TC) > 216 mg/dL.3 In this primary prevention trial, subjects were randomized into three groups: control margarine, margarine + 1.8 g sitostanol ester, or margarine + 2.6 g of sitostanol ester. After 12 months of therapy, the average TC decreased by 0%, 9%, 11% in the control, 1.8 g, and 2.6 g groups, respectively. More importantly, LDL-C decreased by 1%, 12%, and 16%, respectively, over the same period without any significant change in high density lipoprotein (HDL-C) or triglycerides (TG).
In a smaller RCT, 22 postmenopausal women with angiographically documented CAD who were not taking other cholesterol-lowering medication were randomized in a crossover fashion to 3 g sitostanol ester-containing margarine or placebo for seven weeks each.8 In this study, PSE decreased TC by 13% and LDL-C by 20%. The authors also reported 10 other similar women who had been on a stable dose of simvastatin for one year who received 3 g of PSE for 12 weeks in an open trial. Combination therapy augmented the LDL-C lowering effect by 16% compared to simvastatin alone, which decreased LDL-C by 35%.8 Although the number of statin-treated subjects was small and the subset not randomized, another small RCT in type II diabetics confirmed the added benefit of PSE in combination with statins. In this RCT, the addition of 3 g of PSE to 40 mg of pravastatin in controlled diabetics decreased LDL-C by a modest additional 4% (46% statin + PSE vs. 42% statin alone) after seven weeks.10
Finally, a European RCT of 95 subjects directly compared the efficacy of a PSE margarine (Benecol®) against soybean, rice bran, and shea nut-enriched margarines.11 The soybean margarine primarily contained esterified sterols, making it similar to the American product Take Control. At the end of only 3.5 weeks, both Benecol and the soybean margarine when used twice daily significantly and equally reduced LDL-C by 13%, while the other test margarines had no significant lipid lowering effect. These results imply that when used twice a day, both Benecol and Take Control margarines are probably equally effective.
Adverse Effects and Drug Interactions
In all RCTs, sterol and stanol enriched foods at up to 6 g/d were well tolerated, without significant side effects and little dropout at up to 12 months. Over 90% of study participants in one study rated the palatability and texture of a PSE margarine as "good" or "all right."12 In addition, these studies do not report laboratory abnormalities. There are no known drug-PSE interactions. In vitro and in vivo animal studies inconsistently suggest that sitosterol has estrogenic effects and may affect fertility.12 There are no data on its use in pregnancy. Studies have shown that ß-sitosterol is effective in treating benign prostatic hypertrophy, raising the possibility of an estrogenic effect in humans.13 The use of sterols and stanols has been associated with a decrease in serum measures of fat soluble vitamins D, E, A, and K.
These findings however, have not been consistent across RCTs, primarily because tested products have not always been fortified with vitamins. Because these vitamins are transported by lipoproteins, a decrease in cholesterol may also decrease the absolute vitamin levels, while lipid standardized values remain stable. However, Weststrate and Meijer found a decrease of both absolute and lipid-standardized a- and ß-carotenes by 22% and 19% respectively despite vitamin A fortification.11 Another eight-week RCT using vitamin A-fortified margarine found a decrease in absolute values of ß-carotene but not in the carotene/cholesterol ratio.14 Since carotenoids themselves may have positive health effects, this slight decrease of carotene levels needs to be addressed in longer studies.
Studies have not found significant decreases in levels of vitamins D and E when standardized for the reduction in serum cholesterol. A rare, autosomal recessively inherited dyslipidemia called sitosterolemia is characterized by markedly increased absorption of phytosterols in the gut, leading to elevated serum sterol levels, and is clinically manifest by xanthomatosis and premature atherosclerosis. While there are fewer than 50 reported cases, affected patients should limit their dietary intake of sterols. In these patients, unabsorbed stanols should not cause a problem. In normal individuals, one epidemiologic study suggested that high serum phytosterol levels were associated with premature CAD.15 However, a recent analysis of the Scandinavian Simvastatin Survival Study found that higher serum levels of phyto-sterols did not increase the incidence of coronary events in those patients with CAD assigned to placebo.16
Formulations
In the United States, plant sterols and stanols are currently available in margarine spreads, salad dressings, and tablets. (See Table 1.) Soybean-derived sterol esters are the active ingredient in Take Control, while non-absorbable wood-derived stanol esters are the active ingredient in Benecol products. Currently, Take Control comes only in one regular spread and three salad dressings, with a soybean/canola and sunflower oil base. Benecol is available as a regular and light spread with a soybean/canola oil base, as well as four salad dressings. More products such as PSE snack bars are anticipated later next year.
| Table 1-Comparison of commercially available sterol and stanol products | |||||
| Product | Serving Size and Active Ingredient | Manufacturer's Suggested Use | Retail Cost | Calories Per Serving | Total Fat /% Daily Value from Fat |
| Benecol® | 1.5 tsp (1.5 g | 1 pat tid $4.99/21 | servings | 45 | 5 g/14% |
| Spread (McNeil) | sitostanol ester) | ||||
| Take Control | 1 tbsp (1.12 g | 1 tbsp qd to bid | $3.79/16 servings | 50 | 6 g/9% |
| Spread (Lipton) | sitosterol ester) | ||||
| Benecol® Light | 1 tsp (1.5 g | 1 pat tid | $4.99/21 servings | 30 | 3 g/5% |
| Spread | sitostanol ester) | ||||
| Benecol® Ranch | 2 tbsp (1.5 g | 2 tbsp | $4.99/8 oz | 130 | 13 g/20% |
| Salad Dressing | sitostanol ester) | ||||
| Take Control | 2 tbsp (1.12 g | 2 tbsp | $3.79/8 oz | 100 | 8 g/13% |
| Reduced Fat | sitosterol esters) | ||||
| Ranch Dressing | |||||
| Cholestatin | 380 mg phytosterols/ | 1 pill with each | $12.95/90 tablets | 0 | NA |
| (Futurebiotics) | tablet | of three daily meals | |||
| Source: Based on authors' phone conversations wtih company representatives and information from the following Web sites: www.benecol.com, www.takecontrol.com, www.futurebiotics.com, online mail-order sites | |||||
To avoid potential fat-soluble vitamin deficiencies, all products are fortified with vitamins A and E. Although it is possible to sauté and fry with the regular PSE margarine products (Benecol), the plant sterol products (Take Control) and the lower calorie PSE spread (Benecol Light) are not recommended for this purpose, as plant sterols and PSE in the low-fat product break down with extremes of temperature.
Studies of up to one year’s duration have shown that sterol and PSE-containing margarines, when substituted for regular margarine, have not resulted in weight gain.3,8,11,14 This may not be true with the higher fat salad dressings which have never been studied in RCTs. The enriched spreads used in these studies contained low levels of saturated fat (0.5-1 g/serving) and trans fatty acids (0.3-0.8 g/serving), values that are similar to commercially available soft margarines such as Promise.
Dosage
Recommended dosages and available formulations are summarized in Table 1. Esterified sterols are also available in pill form to be ingested with meals. At the recommended doses of 1,200 mg/d, some studies have shown a benefit to these agents, although no published RCTs have specifically addressed the value of sterols in pill form.9 In the United States, there are no currently available stanols in pill form.
Conclusion
Plant sterols and stanols actively and reliably reduce TC and LDL-C by 10-15% in a variety of patient populations. Sterol esters and stanol esters when used bid or tid are probably equally effective and well-tolerated. Because of their proven efficacy and excellent safety profile, sterols and stanols deserve to be incorporated into future NCEP guidelines as part of Step I and II diets or patients with above-target LDL-C. More data are needed on the long-term effects of these agents on carotenoid levels. The potential hormonal effects of sterols, and the possible relationship between serum sterol levels and the development of CAD needs to be studied further in larger clinical trials. Promising early data suggest that PSEs are also safe and effective in combination with statins in lowering serum cholesterol levels.
Recommendation
Plant sterols and stanols should be first-line non- pharmacologic adjuncts to diet and exercise in all patients who do not need to lose weight and who have mild-to-moderate hypercholesterolemia. Because stanols are not absorbed, they might provide an advantage over sterols whose systemic hormonal effects are not yet known. Neither plant sterols nor the low-fat PSEs can be used in cooking. Like other fatty foods, sterol and stanol enriched foods are calorie-dense, and should be substituted for currently used fatty foods. Simply adding these functional foods to a diet already high in fat will likely negate the cholesterol lowering effect of these products.
Which of the following statements is/are true about phyto-sterols and stanols?
a. They decrease total cholesterol.
b. They decrease HDL-C.
c. They decrease LDL-C.
d. They decrease triglycerides.
e. Both a and c.
Dr. Szapary and Dr. Cirigliano are Assistant Professors of Medicine at the University of Pennsylvania School of Medicine in Philadelphia.
References
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2. Sempos CT, et al. Prevalence of high blood cholesterol among US adults. An update based on guidelines from the second report of the National Cholesterol Education Program Adult Treatment Panel. JAMA 1993;269:3009-3014.
3. Miettinen TA, et al. Reduction of serum cholesterol with sitostanol-ester margarine in a mildly hypercholesterolemic population. N Engl J Med 1995;333:1308-1312.
4. Carter NB, Grundy SM. Lowering serum cholesterol with plant sterols and stanols, historical perspectives. In: New Developments in the Dietary Management of High Cholesterol, a Special Report. Postgrad Med 1998;Nov:6-14.
5. Jones PJ, et al. Dietary phytosterols as cholesterol-lowering agents in humans. Can J Physiol Pharmacol 1997;75:217-227.
6. Von Bergmann K, Lutjohann D. Review of the absorption and safety of plant sterols. In: New Developments in the Dietary Management of High Cholesterol, a Special Report. Postgrad Med 1998;Nov:54-59.
7. Ikeda I, Sugano M. Inhibition of cholesterol absorption by plant sterols for mass intervention. Curr Opin Lipidol 1998;9:527-531.
8. Gylling H, et al. Reduction of serum cholesterol in postmenopausal women with previous myocardial infarction and cholesterol malabsorption induced by dietary sitostanol ester margarine: Women and dietary sitostanol. Circulation 1997;96:4226-4231.
9. Mensink RP, Plat J. Efficacy of dietary plant stanols. In: New Developments in the Dietary Management of High Cholesterol, a Special Report. Postgrad Med 1998;Nov:27-31.
10. Gylling H, Miettinen TA. Effects of inhibiting cholesterol absorption and synthesis on cholesterol and lipoprotein metabolism in hypercholesterolemic non-insulin-dependent diabetic men. J Lipid Res 1996;37:1776-1785.
11. Weststrate JA, Meijer GW. Plant sterol-enriched margarines and reduction of plasma total- and LDL-cholesterol concentrations in normocholesterolaemic and mildly hypercholesterolaemic subjects. Eur J Clin Nutr 1998;52:334-343.
12. Plat J, Mensink RP. Safety aspects of dietary plant sterols and stanols. In: New Developments in the Dietary Management of High Cholesterol, a Special Report. Postgrad Med 1998;Nov:32-38.
13. Wilt TJ, et al. Beta-sitosterol for the treatment of benign prostatic hyperplasia: A systematic review. BJU Int 1999;83:976-983.
14. Hallikainen MA, Uusitupa MI. Effects of 2 low-fat stanol ester-containing margarines on serum cholesterol concentrations as part of a low-fat diet in hyper-cholesterolemic subjects. Am J Clin Nutr 1999;69: 403-410.
15. Glueck CJ, et al. Relationships of serum plant sterols (phytosterols) and cholesterol in 595 hypercholesterolemic subjects, and familial aggregation of phyto-sterols, cholesterol, and premature coronary heart disease in hyperphytosterolemic probands and their first-degree relatives. Metabolism 1991;40:842-848.
16. Miettinen TA, et al. Baseline serum cholestanol as a predictor of recurrent coronary events in subgroup of Scandinavian simvastatin survival study. BMJ 1998;316:1127-1130.
January 2000; Volume 3: 6-10
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