[Federal Register: September 8, 2000 (Volume 65, Number 175)]
[Rules and Regulations]
[Page 54685-54739]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr08se00-15]
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Part III
Department of Health and Human Services
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Food and Drug Administration
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21 CFR Part 101
Food Labeling: Health Claims; Plant Sterol/Stanol Esters and Coronary
Heart Disease; Interim Final Rule
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 101
[Docket Nos. 00P-1275 and 00P-1276]
Food Labeling: Health Claims; Plant Sterol/Stanol Esters and
Coronary Heart Disease
AGENCY: Food and Drug Administration, HHS.
ACTION: Interim final rule.
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SUMMARY: The Food and Drug Administration (FDA) is authorizing the use,
on food labels and in food labeling, of health claims on the
association between plant sterol/stanol esters and reduced risk of
coronary heart disease (CHD). FDA is taking this action in response to
a petition filed by Lipton (plant sterol esters petitioner) and a
petition filed by McNeil Consumer Healthcare (plant stanol esters
petitioner). Based on the totality of publicly available evidence, the
agency has concluded that plant sterol/stanol esters may reduce the
risk of CHD.
DATES: This rule is effective September 8, 2000. Submit written
comments by November 22, 2000. The Director of the Office of the
Federal Register approves the incorporation by reference in accordance
with 5 U.S.C. 552(a) and 1 CFR part 51 of certain publications in 21
CFR 101.83(c)(2)(ii)(A)(2) and (c)(2)(ii)(B)(2), as of September 8,
2000.
ADDRESSES: Submit written comments to the Dockets Management Branch
(HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061,
Rockville, MD 20852.
FOR FURTHER INFORMATION CONTACT: Sharon A. Ross, Center for Food Safety
and Applied Nutrition (HFS-832), Food and Drug Administration, 200 C
St. SW., Washington, DC 20204, 202-205-5343.
SUPPLEMENTARY INFORMATION:
I. Background
The President signed into law, on November 8, 1990, the Nutrition
Labeling and Education Act of 1990 (the 1990 amendments) (Public Law
101-535). This new law amended the Federal Food, Drug, and Cosmetic Act
(the act) in number of important ways. One of the most notable aspects
of the 1990 amendments was that they provided procedures whereby FDA is
to regulate health claims on food labels and in food labeling.
In the Federal Register of January 6, 1993 (58 FR 2478), FDA issued
a final rule that implemented the health claim provisions of the act
for conventional foods (hereinafter referred to as the 1993 health
claims final rule). In that final rule, FDA adopted Sec. 101.14 (21 CFR
101.14), which sets out the rules for the authorization of health
claims by regulation and prescribes general requirements for the use of
health claims. Additionally, Sec. 101.70 (21 CFR 101.70) establishes a
process for petitioning the agency to authorize health claims about a
substance-disease relationship (Sec. 101.70(a)) and sets out the types
of information that any such petition must include (Sec. 101.70(d)). On
January 4, 1994 (59 FR 395), FDA issued a final rule applying the
requirements of Secs. 101.14 and 101.70 to health claims for dietary
supplements.
FDA also conducted an extensive review of the evidence on 10
substance-disease relationships listed in the 1990 amendments. As a
result of its review, FDA authorized claims for 8 of these 10
relationships, one of which focused on the relationship between dietary
saturated fat and cholesterol and reduced risk of CHD. CHD is the most
common, most frequently reported, and most serious form of
cardiovascular disease (CVD) (58 FR 2739, January 6, 1993). Further,
while the agency denied the use on food labeling of health claims
relating dietary fiber to reduced risk of CVD (58 FR 2552, January 6,
1993), it authorized a health claim relating fiber-containing fruits,
vegetables, and grain products to a reduced risk of CHD.
In the proposed rule entitled ``Health Claims and Label Statements;
Lipids and Cardiovascular Disease'' (56 FR 60727 at 60727, 60728, and
60732, November 27, 1991), FDA set out the criteria for evaluating
evidence on diet and CVD relationships, including the relationship
between diet and CHD. FDA noted that, because of the public health
importance of CHD, identification of ``modifiable'' risk factors for
CHD had been the subject of considerable research and public policy
attention. The agency also noted that there is general agreement that
elevated blood cholesterol levels are one of the major modifiable risk
factors in the development of CHD. FDA cited Federal Government and
other reviews that concluded that there is substantial epidemiologic
and clinical evidence that high blood levels of total and low density
lipoprotein (LDL) cholesterol are a cause of atherosclerosis
(inadequate blood circulation due to narrowing of the arteries) and
represent major contributors to CHD. Further, factors that decrease
total blood cholesterol and LDL cholesterol will also decrease the risk
of CHD. FDA concluded that it is generally accepted that blood total
and LDL cholesterol levels are major risk factors for CHD, and that
dietary factors affecting blood cholesterol levels affect the risk of
CHD. High intakes of dietary saturated fat and, to a lesser degree, of
dietary cholesterol are consistently associated with elevated blood
cholesterol levels. FDA concluded that the publicly available data
supported an association between diets low in saturated fat and
cholesterol and reduced risk of CHD (58 FR 2739 at 2751).
The agency has authorized other health claims for reducing the risk
of CHD using the aforementioned criteria. In the final rule entitled
``Health Claims; Dietary Fiber and Cardiovascular Disease'' (58 FR
2552), FDA concluded that the publicly available scientific information
supported an association between fruits, vegetables, and grain products
(i.e., foods that are low in saturated fat and cholesterol and that are
good sources of dietary fiber) and reduced risk of CHD through the
intermediate link of blood cholesterol (58 FR 2552 at 2572) (codified
at Sec. 101.77)). In response to two petitions documenting that dietary
consumption of soluble fiber from beta-glucan from oat products and
psyllium seed husk significantly reduced blood cholesterol levels, FDA
authorized health claims for soluble fiber from certain foods and
reduced risk of CHD in Sec. 101.81 (21 CFR 101.81) (62 FR 3584 at 3600,
January 23, 1997, and amended at 62 FR 15343 at 15344, March 31, 1997,
pertaining to beta-glucan from oat products, and 63 FR 8103 at 8119,
February 18, 1998 pertaining to psyllium seed husk). More recently, FDA
authorized a health claim for soy protein and reduced risk of CHD in
Sec. 101.82 (21 CFR 101.82) (64 FR 57700, October 26, 1999). In the
final rule authorizing the claim, the agency concluded, based on the
totality of publicly available scientific evidence, that there is
significant scientific agreement that soy protein, included at a level
of 25 grams (g) per day (d) in a diet low in saturated fat and
cholesterol, can help reduce total and LDL cholesterol levels, and that
such reductions may reduce the risk of CHD (64 FR 57700 at 57713). The
dietary fiber and CVD (56 FR 60582 at 60583 and 60587, November 27,
1991), soluble fiber from beta-glucan from oat products and CHD (61 FR
296 at 298, January 4, 1996), soluble fiber from psyllium seed husk and
CHD (62 FR 28234 at 28236 and 28237, May 22, 1997), and soy protein and
CHD (63 FR 62977 at 62979 and 62980, November 10, 1998) health claim
reviews in the proposed rules were conducted in accordance with the
[[Page 54687]]
1991 criteria for evaluating the evidence between diet and CHD (56 FR
60727 at 60727, 60728, and 60732.
The present rulemaking is in response to two health claim
petitions. One health claim petition concerns the relationship between
plant sterol esters and the risk of CHD, and the other concerns the
relationship between plant stanol esters and the risk of CHD. Although
the plant sterol esters petition characterizes the petitioned substance
as vegetable oil sterol esters, FDA believes it is more accurately
characterized as plant sterol esters. The petition states that
vegetable oil sterol esters consist of esterified plant sterols (Ref.
1, page 3). The petition also mentions that canola oil is one of the
oils used as a source for the sterol component of vegetable oil sterol
esters (Ref. 1, page 82). Canola oil is derived from a seed (rapeseed).
Although seeds are clearly part of the plant kingdom, they are not
ordinarily thought of as vegetables. Therefore, FDA is concerned that
the term ``vegetable oil sterol esters'' may not be understood to cover
esterified sterols from sources like canola oil. Accordingly, the
agency is using the term ``plant sterol esters'' throughout this
document. For purposes of this rule, plant sterol esters and plant
stanol esters will be referred to collectively as ``plant sterol/stanol
esters.''
II. Petitions for Plant Sterol/Stanol Esters and Reduced Risk of
CHD
A. Background
Lipton submitted a health claim petition to FDA on February 1,
2000, requesting that the agency authorize a health claim on the
relationship between consumption of certain plant sterol ester-
containing foods and the risk of CHD (Refs.1 through 4). Specifically,
Lipton requested that spreads and dressings for salad\1\ containing at
least 1.6 grams of plant sterol esters per reference amount customarily
consumed be authorized to bear a health claim about reduced risk of
CHD. On May 11, 2000, the agency sent this petitioner a letter stating
that FDA had decided to file the petition for further review (Ref. 5).
On June 26, 2000, Lipton submitted a request asking FDA to exercise its
authority under section 403(r)(7) of the act (21 U.S.C. 343(r)(7)) to
make any proposed regulation for its petitioned health claim effective
upon publication, pending consideration of public comment and
publication of a final rule (Ref. 6). If the agency does not act, by
either denying the petition or issuing a proposed regulation to
authorize the health claim, within 90 days of the date of filing, the
petition is deemed to be denied unless an extension is mutually agreed
upon by the agency and the petitioner (section 403(r)(4)(a)(i) of the
act and 21 CFR 101.70(j)(3)(iii)). On August 2, 2000, FDA and the plant
sterol ester petitioner agreed to an extension of 30 days, until
September 6, 2000 (Ref. 7).
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\1\ The agency is using the term ``dressings for salad''
throughout this document in lieu of the term ``salad dressing'' used
by the petitioners because the standard of identity for ``salad
dressing'' in Sec. 169.150 (21 CFR 164.150) refers to a limited
class of dressings for salad, i.e., those that contain egg yolk and
meet certain other specifications. ``Salad dressing'' as defined in
Sec. 169.150 does not include a number of common types of dressings
for salad, such as Italian dressing.
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On February 15, 2000, McNeil Consumer Healthcare submitted a health
claim petition to FDA requesting that the agency authorize a health
claim on the relationship between consumption of plant stanol ester-
containing foods and dietary supplements and the risk of CHD (Refs. 8
through 14). On May 25, 2000, the agency sent this petitioner a letter
stating that FDA had decided to file the petition for further review
(Ref. 15). On June 14, 2000, McNeil Consumer Healthcare submitted a
request asking FDA to exercise its authority under section 403(r)(7) of
the act to make any proposed regulation for its petitioned health claim
effective upon publication, pending consideration of public comment and
publication of a final rule (Ref. 16). On July 17, 2000, FDA and the
plant stanol ester petitioner agreed to an extension of the deadline to
publish a proposed regulation until September 6, 2000 (Ref. 17).
In this interim final rule, the agency concludes that a health
claim about plant sterol/stanol esters and reduced risk of CHD should
be authorized under the standard in section 403(r)(3)(B)(i) of the act
and Sec. 101.14(c) of FDA's regulations and should be made effective
upon publication under section 403(r)(7) of the act, pending
consideration of public comment and publication of a final regulation.
The agency is requesting comments on this interim final rule. Firms
should be aware that a final rule on this health claim may differ from
this interim final rule and that they would be required to revise their
labels to conform to any changes adopted in the final rule.
B. Review of Preliminary Requirements for a Health Claim
1. The Substances Are Associated With a Disease for Which the U.S.
Population Is at Risk
Several previous rules establish that CHD is a disease for which
the U.S. population is at risk. These include rules authorizing claims
for dietary saturated fat and cholesterol and risk of CHD Sec. 101.75
(21 CFR 101.75)); fiber-containing fruits, vegetables, and grain
products and risk of CHD (Sec. 101.77); soluble fiber from certain
foods and risk of CHD (Sec. 101.81); and soy protein and risk of CHD
(Sec. 101.82). FDA stated in these rules that CHD remains a major
public health problem and the number one cause of death in the United
States. Despite the decline in deaths from CHD over the past 30 years,
this disease is still exacting a tremendous toll in morbidity (illness
and disability) and mortality (premature deaths) (Refs. 18 through 20).
There are more than 500,000 deaths each year for which CHD is the
primary cause, and another 250,000 deaths for which CHD is a
contributing cause. About 20 percent of adults (male and female; black
and white) ages 20 to 74 years have blood total cholesterol (or serum
cholesterol) levels in the ``high risk'' category (total cholesterol
greater than (>) 240 milligrams (mg) / deciliter (dL) and LDL
cholesterol > 160mg/dL) (Ref. 21). Another 31 percent have ``borderline
high'' cholesterol levels (total cholesterol between 200 and 239 mg/dL
and LDL cholesterol between 130 and 159 mg/dL) in combination with two
or more other risk factors for CHD.
CHD has a significant effect on health care costs. In 1999, total
direct costs related to CHD were estimated at $53.1 billion, and
indirect costs from loss of productivity due to illness, disability,
and premature deaths from this disease were an estimated $46.7 billion
(Ref. 22). Based on these facts, FDA concludes that, as required in
Sec. 101.14(b)(1), CHD is a disease for which the U.S. population is at
risk.
2. The Substances Are Food
The substances that are the subject of this interim final rule are
plant sterol esters and plant stanol esters (Refs. 1 through 4 and 8
through 14).
a. Plant sterol esters. The substance that is the subject of the
plant sterol ester petition is a mixture of plant sterols esterified to
food-grade fatty acids. The sterols are primarily (beta-sitosterol,
campesterol, and stigmasterol and are extracted from plant sources
(Ref. 1, page 6). Plant sterols occur widely throughout the plant
kingdom
[[Page 54688]]
and are present in many edible fruits, vegetables, nuts, seeds,
cereals, and legumes (Refs. 23 and 24). The plant sterols in foods may
occur as either the free sterol or esterified with a fatty acid.
Several studies have estimated dietary plant sterol intake. From a
population in the Los Angeles area, Nair et al. (Ref. 25) found that
plant sterol (beta-sitosterol and stigmasterol) intake ranged from 77.9
mg/d in the general population to 343.6 mg/d in lacto-ovo vegetarians.
The 1991 British diet was estimated to contain about 158 mg/d of
sterols (beta-sitosterol, stigmasterol, and campesterol) (Ref. 26).
Scandinavian vegetarians consume, on average, 513 mg/d and
nonvegetarians 398 mg/d (Ref. 27). Plant sterol intake in the Japanese
diet has been estimated at 373 mg/d (Ref. 28). In an analysis of diets
of participants in the Seven Countries Study, deVries et al. (Ref. 29)
found plant sterol intake (sitosterol, stigmasterol and campesterol) to
range from 170 mg/d among U.S. railroad workers to 358 mg/d in Corfu,
Greece. In a review, Ling and Jones (Ref. 30) estimated average U.S.
intake at 250 mg/d; it was speculated that this level was doubled among
vegetarians. Thus, plant sterols are a constituent of the diet for
Americans and other population groups.
According to the plant sterol ester petitioner, the solubility of
free sterols in oil is only 2 percent, but the solubility of sterol
esters in oil exceeds 20 percent (Ref. 1, pages 14 and 99). Therefore,
the free plant sterols are esterified with fatty acids from sunflower
to improve solubility. The petitioner also notes that improved
solubility of plant sterols creates a palatable product and is
associated with more uniform distribution in the product and in the
gastrointestinal tract (Ref. 1, page 14). In vegetable oils, typically
between 25 and 80 percent of the sterol is in the ester form (Refs. 31
through 34). One gram of plant sterols is equivalent to about 1.6 g of
plant sterol esters (Refs. 35 and 36).
Under Sec. 101.14(b)(3)(i), the substance that is the subject of a
health claim must contribute taste, aroma, or nutritive value, or any
other technical effect listed in Sec. 170.3(o) (21 CFR 170.3(o)), to
the food and must retain that attribute when consumed at the levels
that are necessary to justify a claim. Plant sterol esters do not
contribute taste, aroma, or any other technical effect listed in
Sec. 170.3(o), and thus the plant sterol esters must contribute
nutritive value to meet the requirement in Sec. 101.14(b)(3)(i).
The term `nutritive value' is defined in Sec. 101.14(a)(3) as
``value in sustaining human existence by such processes as promoting
growth, replacing loss of essential nutrients, or providing energy.''
In the proposed rule entitled ``Labeling; General Requirements for
Health Claims for Food'' (56 FR 60537, November 27, 1991), FDA proposed
this definition and explained its interpretation of nutritive value in
the context of whether a substance is a food and thus appropriately the
subject of a health claim (56 FR 60537 at 60542). The agency indicated
that the definition was formulated based on the common meaning of the
words that make up the term ``nutritive value.'' The agency also added
that use of the phrase ``such processes as'' in the definition of
nutritive value was intended to provide a measure of flexibility that
the agency believed would be necessary in evaluating future petitions.
In the final rule adopting the proposed definition, the agency noted
that the evaluation of the nutritive value of substances would be done
on a case-by-case basis to best ensure that the definition retains its
intended flexibility (58 FR 2478 at 2488). In a subsequent final rule
on health claims for dietary supplements (59 FR 395 at 407), FDA
further explained that nutritive value ``includes assisting in the
efficient functioning of classical nutritional processes and of other
metabolic processes necessary for the normal maintenance of human
existence.''
The scientific evidence suggests that the cholesterol-lowering
effect of plant sterol esters is achieved through an effect on the
digestive process (Ref. 1, pages 62 through 64). The digestive process
is one of the metabolic processes necessary for the normal maintenance
of human existence. Therefore, the agency concludes that the
preliminary requirement of Sec. 101.14(b)(3)(i) is satisfied.
b. Plant stanol esters. The substance that is the subject of the
plant stanol ester petition is a mixture of plant stanols esterified to
food-grade fatty acids. The stanols are primarily sitostanol and
campestanol and may be derived from hydrogenated plant sterol mixtures
or extracted from plant sources (Ref. 8, page 18). Sitostanol and
campestanol occur naturally in small quantities in the lipid fractions
of cereal grains such as wheat, rye, and corn (Refs. 37 through 39) and
in vegetable oils such as corn and olive oil (Refs. 40 and 41). The
average western diet provides 20 to 50 mg of plant stanols daily (Ref.
42).
According to the plant stanol ester petitioner, esterification of
free stanols with fatty acids renders plant stanols readily soluble in
foods and makes an effective vehicle for delivery of plant stanols to
the small intestine (Ref. 8, page 9). One gram of wood-derived plant
stanols is equivalent to about 1.7 g of plant stanol esters (Ref. 43),
and 1 g of vegetable oil plant stanols is equivalent to about 1.8 g of
plant stanol esters (Ref. 43).
As discussed in section II.B.2.a of this document, the substance
that is the subject of a health claim must contribute taste, aroma, or
nutritive value, or any other technical effect listed in Sec. 170.3(o),
to the food and must retain that attribute when consumed at levels that
are necessary to justify a claim (Sec. 101.14(b)(3)(i)). Plant stanol
esters do not contribute taste, aroma or any other technical effect
listed in Sec. 170.3(o) and thus must contribute nutritive value to
meet the requirement in Sec. 101.14(b)(3)(i). The term ``nutritive
value'' is defined in Sec. 101.14(a)(3) as ``value in sustaining human
existence by such processes as promoting growth, replacing loss of
essential nutrients, or providing energy.''
The scientific evidence suggests that the cholesterol-lowering
effect of plant stanol esters is achieved through an effect on the
digestive process (Ref. 8, pages 11 through 12). As discussed in
section II.B.2.a of this document and in the final rule on health
claims for dietary supplements (59 FR 395 at 407), nutritive value
includes assisting in the efficient functioning of classical
nutritional processes and of other metabolic processes necessary for
the normal maintenance of human existence, such as digestive processes.
Therefore, the agency concludes that the preliminary requirement of
Sec. 101.14(b)(3)(i) is satisfied.
3. The Substances Are Safe and Lawful
a. Plant sterol esters. The plant sterol ester petitioner asserts
that plant sterol esters are generally recognized as safe (GRAS) for
certain uses. In a submission dated January 11, 1999, the petitioner
informed FDA of its conclusion that plant sterol esters are GRAS for
use in vegetable oil spreads at levels up to 20 percent (corresponding
to 1.6 g of plant sterol esters per serving) to supplement the
nutritive value of the spread, and to help structure the fat phase and
reduce the fat and water content of the spread. The January 11, 1999,
submission included the supporting data on which this conclusion was
based. FDA responded to this submission in a letter dated April 30,
1999 (Ref. 44). In its response, the agency stated, ``Based on its
evaluation, the agency has no questions at this time regarding Lipton's
conclusion that vegetable oil sterol esters are GRAS under the intended
conditions of use. Furthermore, FDA is not aware of any scientific
evidence that
[[Page 54689]]
vegetable oil sterol esters would be harmful. The agency has not,
however, made its own determination regarding the GRAS status of the
subject use of vegetable oil sterol esters'' (Ref. 44). In a letter
dated September 24, 1999, the petitioner informed FDA of an additional
use of plant sterol esters in dressings for salad (Ref. 45). The letter
contained additional safety information to support the new use.
The agency notes that authorization of a health claim for a
substance should not be interpreted as affirmation that the substance
is GRAS. A review of Lipton's January 11, 1999, submission and of its
September 24, 1999, letter to the agency, however, reveals significant
evidence supporting the safety of the use of plant sterol esters at the
levels necessary to justify a health claim. Moreover, FDA is not aware
of any evidence that provides a basis to reject the petitioner's
position that the use of plant sterol esters in spreads and dressings
for salad up to 1.6 g/serving is safe and lawful. As discussed in
section V.B of this document, the level of plant sterol esters
necessary to justify a claim is 1.3 g per day. Therefore, FDA concludes
that the petitioner has satisfied the requirement of
Sec. 101.14(b)(3)(ii) to demonstrate that the use of plant sterol
esters in spreads and dressings for salad at the levels necessary to
justify a claim is safe and lawful.
b. Plant stanol esters. Under the health claim petition process,
FDA evaluates whether the substance is ``safe and lawful'' under the
applicable food safety provisions of the act (Sec. 101.14(b)(3)(ii)).
For conventional foods, this evaluation involves considering whether
the ingredient that is the source of the substance is GRAS, listed as a
food additive, or authorized by a prior sanction issued by FDA (see
Sec. 101.70(f)). Dietary ingredients in dietary supplements, however,
are not subject to the food additive provisions of the act (see section
201(s)(6) of the act (21 U.S.C. 321(s)(6)). Rather, they are subject to
the new dietary ingredient provisions in section 413 of the act (21
U.S.C. 350b) and the adulteration provisions in section 402 of the act
(21 U.S.C. 342). The term ``dietary ingredient'' is defined in section
201(ff)(1) of the act and includes vitamins; minerals; herbs and other
botanicals; dietary substances for use by man to supplement the diet by
increasing the total daily intake; and concentrates, metabolites,
constituents, extracts, and combinations of the preceding ingredients.
A ``new dietary ingredient'' is a dietary ingredient that was not
marketed in the United States before October 15, 1994 (section 413(c)
of the act). If a dietary supplement contains a new dietary ingredient
that has not been present in the food supply as an article used for
food in a form in which the food has not been chemically altered,
section 413(a)(2) of the act requires the manufacturer or distributor
of the supplement to submit to FDA, at least 75 days before the dietary
ingredient is introduced or delivered for introduction into interstate
commerce, information that is the basis on which the manufacturer or
distributor has concluded that a dietary supplement containing such new
dietary ingredient will reasonably be expected to be safe. FDA reviews
this information to determine whether it provides an adequate basis for
such a conclusion. Under section 413(a)(2) of the act, there must be a
history of use or other evidence of safety establishing that the
dietary ingredient, when used under the conditions recommended or
suggested in the labeling of the dietary supplement, will reasonably be
expected to be safe. If FDA believes that this requirement has not been
met, the agency responds to the notification within 75 days from the
date of its receipt. Otherwise, no response is sent. If a new dietary
ingredient notification has been submitted and a history of use or
other evidence of safety exists that establishes a reasonable
expectation of safety, the new dietary ingredient may be lawfully
marketed in dietary supplements 75 days after the notification is
submitted.
As previously noted, the plant stanol ester petitioner requested
authorization to make a health claim about plant stanol esters and the
risk of CHD in the labeling of both conventional foods and dietary
supplements. Because the standards under which the safety and legality
of conventional foods and dietary supplements are evaluated differ, the
agency is discussing these two proposed uses separately.
i. Conventional foods. The plant stanol ester petitioner asserts
that plant stanol esters are GRAS. In a submission dated February 18,
1999, the petitioner informed FDA of its conclusion that plant stanol
esters are GRAS for use as a nutrient in spreads at a level of 1.7g of
plant stanol esters per serving of spread. The February 18, 1999,
submission included the supporting data on which this conclusion was
based. FDA responded to this submission in a letter dated May 17, 1999
(Ref. 46). In its response, the agency stated, ``Based on its
evaluation, the agency has no questions at this time regarding McNeil's
conclusion that plant stanol esters are GRAS under the intended
conditions of use. Furthermore, FDA is not aware of any scientific
evidence that plant stanol esters would be harmful. The agency has not,
however, made its own determination regarding the GRAS status of the
subject use of plant stanol esters'' (Ref. 46). The petitioner's GRAS
determination applies to plant stanol esters whose stanol components
are prepared by the hydrogenation of commercially available plant
sterol blends, which are obtained as distillates from vegetable oils or
as byproducts of the kraft paper pulping process (Ref. 46). In letters
dated July 21, 1999, and October 13, 1999, the petitioner informed FDA
of additional uses of plant stanol esters in dressings for salad and
snack bars (Refs. 47 and 48).
The agency notes that authorization of a health claim for a
substance should not be interpreted as affirmation that the substance
is GRAS. A review of McNeil's February 18, 1999, submission, however,
reveals significant evidence supporting the safety of the use of plant
stanol esters at the levels necessary to justify a health claim.
Moreover, FDA is not aware of any evidence that provides a basis to
reject the petitioner's position that the use of plant stanol esters in
spreads, dressings for salad, snack bars, and other foods is safe and
lawful. FDA therefore concludes that the petitioner has satisfied the
requirement of Sec. 101.14(b)(3)(ii) to demonstrate that the use of
plant stanol esters in conventional foods at the levels necessary to
justify a claim is safe and lawful.
ii. Dietary supplements. The petitioner submitted a new dietary
ingredient notification for plant stanol esters on August 19, 1999.\2\
The new dietary ingredient notification contained several papers that
reported the results of studies conducted in humans to test
hypocholesterolemic effects of plant stanol esters as well as a
reference to the plant stanol ester petitioner's GRAS submission of
February 18, 1999, and the agency's response to this submission in a
letter dated May 17, 1999 (Ref. 46). In FDA's judgment, the studies
submitted in the plant stanol esters new dietary ingredient
notification and GRAS submission appeared to provide an adequate basis
that a dietary
[[Page 54690]]
supplement containing plant stanol esters would reasonably be expected
to be safe. Therefore, the agency did not respond to the new dietary
ingredient notification. Because the safety standard in section
413(a)(2) of the act has been met and the new dietary ingredient
notification was submitted more than 75 days ago, plant stanol esters
may now be lawfully marketed as dietary ingredients in dietary
supplements. Therefore, FDA concludes that the petitioner has satisfied
the requirement of Sec. 101.14(b)(3)(ii) to demonstrate that the use of
plant stanol esters in dietary supplements at the levels necessary to
justify a claim is safe and lawful.
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\2\ The notification states that McNeil does not believeplant
stanol esters to be a new dietary ingredient requiring submission of
a premarket notification, but that McNeil is voluntarily submitting
the information that would be required as part of such a
notification ``for the purpose of providing the Food and Drug
Administration with advance notice concerning its dietary
ingredient'' (Ref. 49).
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III. Review of Scientific Evidence of the Substance-Disease
Relationship
A. Basis for Evaluating the Relationship Between Plant Sterol/Stanol
Esters and CHD
FDA's review examined the relationship between plant sterol/stanol
esters and CHD by focusing on the effects of dietary intake of this
substance on blood cholesterol levels and on the risk of developing
CHD. In the 1991 lipids-CVD and dietary fiber-CVD health claim
proposals, the agency set forth the scientific basis for the
relationship between dietary substances and CVD (56 FR 60727 at 60728
and 56 FR 60582 at 60583). In those documents, the agency stated that
there are many risk factors that contribute to the development of CVD,
and specifically CHD, one of the most serious forms of CVD and among
the leading causes of death and disability. The agency also stated that
there is general agreement that elevated blood cholesterol levels are
one of the major modifiable risk factors in the development of CVD and,
more specifically, CHD.
Several Federal agencies and scientific bodies that have reviewed
the matter have concluded that there is substantial epidemiologic
evidence that high blood levels of total cholesterol and LDL
cholesterol are a cause of atherosclerosis and represent major
contributors to CHD (56 FR 60727 at 60728, 56 FR 60582 at 60583, Refs.
18 through 20). Factors that decrease total cholesterol and LDL
cholesterol will also tend to decrease the risk of CHD. High-intakes of
saturated fat and, to a lesser degree, of dietary cholesterol are
associated with elevated blood total and LDL cholesterol levels (56 FR
60727 at 60728). Thus, it is generally accepted that blood total
cholesterol and LDL cholesterol levels can influence the risk of
developing CHD, and, therefore, that dietary factors affecting these
blood cholesterol levels affect the risk of CHD (Refs. 18 through 20).
When considering the effect that the diet or components of the diet
have on blood (or serum) lipids, it is important to consider the effect
that these factors may have on blood levels of high density lipoprotein
(HDL) cholesterol. HDL cholesterol appears to have a protective effect
against CHD because it is involved in the regulation of cholesterol
transport out of cells and to the liver, from which it is ultimately
excreted (Refs. 18 and 50).
For these reasons, the agency based its evaluation of the
relationship between consumption of plant sterol/stanol esters and the
risk of CHD primarily on changes in blood total and LDL cholesterol
resulting from dietary intervention with plant sterol/stanol ester-
containing products. A secondary consideration was that beneficial
changes in total and LDL cholesterol should not be accompanied by
potentially adverse changes in HDL cholesterol. This focus is
consistent with that used by the agency in deciding on the dietary
saturated fat and cholesterol and CHD health claim, Sec. 101.75 (56 FR
60727 and 58 FR 2739); the fiber-containing fruits, vegetables, and
grain products and CHD claim, Sec. 101.77 (56 FR 60582 and 58 FR 2552);
the soluble fiber from certain foods and CHD claim, Sec. 101.81 (61 FR
296, 62 FR 3584, 62 FR 28234, and 63 FR 8119) and the soy protein and
CHD claim, Sec. 101.82 (63 FR 62977 and 64 FR 57700).
B. Review of Scientific Evidence
1. Evidence Considered in Reaching the Decision
a. Plant sterol esters and CHD. The plant sterol esters petitioner
submitted 15 scientific studies (Refs. 51 through 60, 61 and 62 (1
study), 63 and 64 (1 study), and 65 through 67) evaluating the
relationship between plant sterol esters or plant sterols and blood
cholesterol levels in humans. The studies submitted were conducted
between 1953 and 2000. The petition included tables that summarized the
outcome of each of the studies and a summary of the evidence.
The plant sterol ester petitioner states that since plant sterol
esters are hydrolyzed to free sterols and fatty acids in the
gastrointestinal tract (see Refs. 68 through 70), and free sterols are
the active moiety of plant sterol esters (see Refs. 69 and 71), the
literature on free plant sterols has a direct bearing on this petition
(Ref. 1, page 14). The agency agrees that the active moiety of the
plant sterol ester is the plant sterol and has concluded that studies
of the effectiveness of free plant sterols in blood cholesterol
reduction are relevant to the evaluation of the evidence in the plant
sterol esters petition. Accordingly, FDA included such studies in its
evaluation of the relationship between plant sterol esters and reduced
risk of CHD if they met the study selection criteria specified in
section III.B.2 of this document.
In several previous diet and CHD health claim rulemakings, the
agency began its review of scientific evidence in support of the health
claim by considering those studies that were published since 1988, the
date of publication of the ``Surgeon General's Report on Nutrition and
Health'' (Ref. 18), which is the most recent and comprehensive Federal
review of the scientific evidence on dietary factors and CHD. That
approach was not possible in this instance, however, as the ``Surgeon
General's Report on Nutrition and Health'' does not discuss the effects
of dietary plant sterols or plant sterol esters on blood cholesterol or
CHD. A discussion of the role of dietary sterols in CHD does appear in
another roughly contemporaneous source, the National Academy Press
publication ``Diet and Health: Implications for Reducing Chronic
Disease Risk'' (Ref. 19), which was issued in 1989. That publication
states:
Long ago, plant sterols (beta-sitosterol and related compounds)
were found to prevent absorption of dietary cholesterol (Best et al.,
1955; Farquhar and Sokolow, 1958; Farquhar et al., 1956; Lees et al.,
1977; Peterson et al., 1959), apparently by blocking absorption of
cholesterol in the intestine (Davis, 1955; Grundy and Mok, 1977;
Jandacek et al., 1977; Mattson et al., 1977). More recent reports
indicate that these compounds may be more effective in small doses than
previously believed (Mattson et al., 1982).
This discussion highlights the previous and current emphasis of
research on the topic. Investigations in the 1950's reported the
effects of plant sterols on cholesterol absorption using animal models
and in a few human studies; work in the 1970's examined beta-sitosterol
in the form of a drug product to lower cholesterol in humans. In fact,
beta-sitosterol is approved for use as a drug to lower cholesterol
(Refs. 72 and 73). More recent research has focused on smaller amounts
of plant sterols that are solubilized as fatty acid esters of plant
sterols in food products. The agency considers the older research to be
of little relevance to the petitioned health claim because it concerned
forms and amounts of the substance different from those that are the
subject of the
[[Page 54691]]
petition. Therefore, FDA included in its review only those studies
published from 1982 (the date the National Academy Press publication
refers to for the more recent research reports (Ref. 19)) to the
present among those submitted by the petitioner (Refs. 51, 52, 57, 58,
61 and 62 (1 study), 63 and 64 (1 study), 65, and 67). In addition to
eight studies submitted by the petitioner, FDA also considered two
other studies (Refs. 74 and 75) concerning the effects of plant sterol
esters on blood cholesterol. These two studies were identified by a
literature search (Ref. 76) performed to verify that the totality of
publicly available scientific evidence had been submitted to the
agency.
In addition to the human studies previously discussed, the plant
sterol esters petition also presented some findings from studies that
employed animal models. Human studies are weighted most heavily in the
evaluation of evidence on a diet and disease relationship; animal model
studies can be considered as supporting evidence but cannot serve as
the sole basis for establishing that a diet and disease relationship
exists. Because there were enough well-controlled studies in humans to
evaluate the relationship between plant sterol esters and CHD, FDA did
not closely review the studies in animals.
b. Plant stanol esters and CHD. The plant stanol ester petitioner
submitted 21 scientific studies (Refs. 63 and 64 (1 study), and 67, 77
through 80, 81 and 82 (1 study), and 83 through 96) evaluating the
relationship between plant stanol esters or plant stanols and blood
cholesterol levels in humans. The studies submitted were conducted
between 1993 and 2000. The petition included tables that summarized the
outcome of each of the studies and a summary of the evidence.
Stanol esters are hydrolyzed in the gastrointestinal tract to fatty
acids and free stanols, and investigators believe there is
physiological equivalence of free stanols and stanol esters in
affecting blood cholesterol concentrations. Accordingly, the agency
concludes that studies of the effectiveness of free plant stanols in
blood cholesterol reduction are relevant to the evaluation of the
relationship between plant stanol esters and reduced risk of CHD when
such studies meet the study selection criteria specified in section
III.B.2 of this document.
In several previous diet and CHD health claim rulemakings, the
agency began its review of scientific evidence in support of the health
claim by considering those studies that were published since 1988, the
date of publication of the ``Surgeon General's Report on Nutrition and
Health'' (Ref. 18), which is the most recent and comprehensive Federal
review of the scientific evidence on dietary factors and CHD. The
``Surgeon General's Report on Nutrition and Health,'' however, did not
discuss the effects of dietary plant stanol esters on blood cholesterol
or CHD. Although a discussion of the role of dietary sterols in CHD
appears in the 1989 National Academy Press publication ``Diet and
Health: Implications for Reducing Chronic Disease Risk,'' there is no
mention of plant stanol esters in this publication (Ref. 19). In fact,
research on the cholesterol-lowering capacity of plant stanol esters
has been a recent development. The agency used 1992 as a starting point
for its scientific evaluation, because this is the year that the
earliest study evaluating the effects of plant stanol esters on blood
cholesterol was published. The agency included in its review 24 studies
published from 1992 to present that were submitted by the petitioner or
otherwise identified (Refs. 58, 63 and 64 (1 study), 67, 74, 77 through
80, 81 and 82 (1 study), and 83 through 97). Of these, 21 studies
(Refs. 63 and 64 (1 study), 67, 77 through 80, 81 and 82 (1 study), and
83 through 96) were submitted by the petitioner. Two studies (Refs. 74
and 97) were identified by a literature search (Ref. 76) performed to
verify that the totality of publicly available scientific evidence had
been submitted to the agency. In addition, one recently published study
that was submitted in the plant sterol esters petition included
administration of plant stanol esters (Ref. 58). This study was
included in the plant stanol ester review.
In addition to the published studies previously discussed, the
plant stanol ester petitioner submitted a summary of 10 unpublished
studies (Ref. 8, pages 59 through 69). The unpublished studies did not
weigh heavily in the agency's review because health claims are
authorized based on the totality of publicly available scientific
evidence (see section 403(r)(3)(B)(i) of the act and Sec. 101.14(c))
and because the summaries of these studies lacked sufficient detail on
study design and methodologies.
2. Criteria for Selection of Human Studies on Plant Sterol/Stanol
Esters and CHD
The criteria that the agency used to select the most pertinent
studies in both health claim petitions were consistent with those that
the agency used in evaluating the relationship between other substances
and CHD. These criteria were that the studies: (1) Present data and
adequate descriptions of the study design and methods; (2) be available
in English; (3) include estimates of, or enough information to
estimate, intakes of plant sterols or stanols and their esters; (4)
include direct measurement of blood total cholesterol and other blood
lipids related to CHD; and (5) be conducted in persons who represent
the general U.S. population. In the case of criterion (5), these
persons can be considered to be adults with blood total cholesterol
levels less than 300 mg/dL, as explained below.
In a previous rulemaking (62 FR 28234 at 28238 and 63 FR 8103 at
8107), the agency concluded that hypercholesterolemic study populations
were relevant to the general population because, based on data from the
National Health and Nutrition Examination Surveys (NHANES) III, the
prevalence of individuals with elevated blood cholesterol (i.e., 200
mg/dL or greater) is high, i.e., approximately 51 percent of adults
(Ref. 21). The proportion of adults having moderately elevated blood
cholesterol levels (i.e., between 200 and 239 mg/dL) was estimated to
be approximately 31 percent, and the proportion of adults with high
blood cholesterol levels (240 mg/dL or greater) was estimated to be
approximately 20 percent (Ref. 21). It is also estimated that 52
million Americans 20 years of age and older would be candidates for
dietary intervention to lower blood cholesterol (Ref. 21). As the
leading cause of death in this country, CHD is a disease for which the
general U.S. population is at risk. Since more than half of American
adults have mildly to moderately elevated blood cholesterol levels, FDA
considers studies in these populations to be representative of a large
segment of the general population. Accordingly, in this rule, the
agency has reviewed and considered the evidence of effects of plant
sterol/stanol esters on blood cholesterol in mildly and moderately
hypercholesterolemic subjects as well as subjects with cholesterol
levels in the normal range.
In selecting human studies for review, the agency excluded studies
that were published in abstract form because they lacked sufficient
detail on study design and methodologies, and because they lacked
necessary primary data. Studies using special population groups, such
as adults with very high serum cholesterol (mean greater than 300 mg/
dL), children with hypercholesterolemia, and persons who had already
experienced a myocardial infarction (heart attack) or
[[Page 54692]]
who had a diagnosis of noninsulin dependent diabetes mellitus, were
also excluded because of questions about their relevance to the general
U.S. population.
3. Criteria for Evaluating the Relationship Between Plant Sterol/Stanol
Esters and CHD
The evaluation of study design, protocol, measurement, and
statistical issues for individual studies serves as the starting point
from which FDA determines the overall strengths and weaknesses of the
data and assesses the weight of the evidence. FDA's ``Guidance for
Industry: Significant Scientific Agreement in the Review of Health
Claims for Conventional Foods and Dietary Supplements'' articulates the
agency's approach to evaluating studies supporting diet/disease
relationships (Ref. 98). The criteria that the agency used in
evaluating the studies for this rulemaking include: (1) Adequacy and
clarity of the design (e.g., was the methodology used in the study
clearly described and appropriate for answering the questions posed by
the study?); (2) population studied (e.g., was the sample size large
enough to provide sufficient statistical power to detect a significant
effect?); (3) assessment of intervention or exposure and outcomes
(e.g., was the dietary intervention or exposure well defined and
appropriately measured?); and (4) statistical methods (e.g., were
appropriate statistical analyses applied to the data?).
The general study design characteristics for which the agency
looked included selection criteria for subjects, appropriateness of
controls, randomization of subjects, blinding, statistical power of the
studies, presence of recall bias and interviewer bias, attrition rates
(including reasons for attrition), potential for misclassification of
individuals with regard to dietary intakes, recognition and control of
confounding factors (for example, monitoring body weight and control of
weight loss), and appropriateness of statistical tests and comparisons.
The agency considered whether the intervention studies that it
evaluated had been of long enough duration, greater than or equal to 3
weeks duration, to ensure reasonable stabilization of blood lipids.
As discussed above, dietary saturated fat and cholesterol affect
blood cholesterol levels (Refs. 19 and 20). Previous reviews by FDA and
other scientific bodies have generally concluded that, in persons with
relatively higher baseline levels of blood cholesterol, responses to
dietary intervention tend to be of a larger magnitude than is seen in
persons with more normal blood cholesterol levels (56 FR 60582 at 60587
and Refs. 19 and 20). To take into account these factors, FDA
separately evaluated studies on mildly to moderately
hypercholesterolemic individuals (persons with elevated blood total
cholesterol levels of 200 to 300 mg/dL) and studies on
normocholesterolemic individuals (persons with blood total cholesterol
levels in the normal range ( 200 mg/dL)). FDA also separately evaluated
studies in which the effects of plant sterol/stanol esters were
evaluated as part of a ``typical'' American diet (approximately 37
percent of calories from fat, 13 percent of calories from saturated
fat, and more than 300 mg of cholesterol daily) and studies in which
the test protocols incorporated a dietary regimen that limits fat
intake such as the National Heart, Lung, and Blood Institute's National
Cholesterol Education Program Step I Diet (intake of 8 to 10 percent of
total calories from saturated fat, 30 percent or less of calories from
total fat, and cholesterol less than 300 mg/d) (Ref. 99).
C. Review of Human Studies
1. Studies Evaluating the Effects of Plant Sterol Esters on Blood
Cholesterol
As discussed in section III. B.1.a of this document, FDA reviewed
10 human clinical studies on plant sterol esters or other plant sterols
(Refs. 51, 52, 57, 58, 61 and 62 (1 study), 63 and 64 (1 study), 65,
67, and 74 and 75). Of these, nine met the selection criteria listed in
section III.B.2 of this document (Refs. 51, 57, 58, 61 and 62 (1
study), 63 and 64 (1 study), 65, 67 and 74 and 75). These studies are
summarized in table 1 at the end of this document and discussed below.
The remaining study (Ref. 52) failed to meet the inclusion criteria
because the population studied (children with familial
hypercholesterolemia) was not representative of the general U.S.
population. As supporting evidence, the results of one research
synthesis study (Ref. 100) that included a number of the plant sterol
ester studies submitted in the petition are discussed in section
III.C.1.d of this document.
Studies typically report the amount of free plant sterol consumed
rather than the amount of plant sterol ester administered. Where
possible, we report both the amount of plant sterol ester and the
equivalent free sterol.
(a) Hypercholesterolemics (serum cholesterol 300 mg/dL): low
saturated fat and cholesterol diets. One study was submitted as a draft
in the plant sterol esters petition because it has been submitted for
publication, but has not yet been published other than in abstract form
(Ref. 62). FDA reviewed this study but considers the results
preliminary until a full report of the study has been published. The
preliminary results in this study (Refs. 61 and 62 (1 study)) showed a
cholesterol-reducing effect of plant sterol esters in
hypercholesterolemic subjects who consumed soybean oil sterol esters as
part of a low saturated fat and low cholesterol diet. In this study,
224 men and women with mild-to-moderate hypercholesterolemia instructed
to follow a National Cholesterol Education Program Step I diet were
randomly assigned to one of three groups: (1) control reduced-fat
spread, (2) reduced-fat spread containing 1.76 g/d of plant sterol
esters (1.1 g/d free plant sterols) (low intake group), or (3) reduced-
fat spread containing 3.52 g/d of plant sterol esters (2.2 g/d free
plant sterols) (high-intake test group). All subjects consumed 14 g/d
of spread in two 7 g servings/day, with food. Subjects in the low- and
high-intake groups who consumed ``80 percent of scheduled servings had
decreases in serum total cholesterol of 5.2 and 6.6 percent, and LDL
cholesterol of 7.6 and 8.1 percent, respectively, versus control
(p0.001). The difference between the two test groups with regard to
serum total and LDL cholesterol levels was not statistically
significant. HDL cholesterol responses did not differ among the groups.
These preliminary results indicate that a plant sterol ester-containing
reduced-fat spread, in a diet low in saturated fat and cholesterol, can
reduce cholesterol.
(b) Hypercholesterolemics (serum cholesterol 300 mg/dL):
``typical'' or ``usual'' diets. Four studies (Refs. 57, 58, 67, and 74)
show a relationship between consumption of plant sterols and reduced
blood cholesterol in hypercholesterolemic subjects consuming diets
within the range of a typical American diet. A fifth study (Refs. 63
and 64 (1 study)) shows inconclusive results.
Jones et al. (Ref. 58) conducted a controlled feeding crossover
study in which diets were based on a fixed-food North American diet
formulated to meet Canadian recommended nutrient intakes. This study
reported significantly lower plasma total cholesterol (9.1 percent, p
0.005) and LDL cholesterol (13.2 percent, p 0.02) in male subjects
consuming 2.94 g/d vegetable oil sterol esters (1.84 g/d free plant
sterols delivered in 23 g of margarine each day; daily margarine doses
were divided into three equal
[[Page 54693]]
portions and added to each meal) for 21 days compared to 21 days on
control margarine. Plasma HDL cholesterol did not differ across groups
and there was no significant weight change shown by the subjects while
consuming any of the margarine mixtures.
Hendriks et al. (Ref. 57) reported the effects of feeding three
different levels of vegetable oil sterol esters (1.33, 2.58, and 5.18
g/d corresponding to 0.83, 1.61, and 3.24 g/d free plant sterols,
respectively) incorporated in spreads (25 g/d of spread replaced an
equivalent amount of the spread(s) habitually used; one-half was
consumed at lunch, one-half at dinner) in apparently healthy
normocholesterolemic and mildly hypercholesterolemic subjects using a
randomized, double-blind placebo-controlled balanced incomplete Latin
square design with five treatments and four periods. The vegetable oil
sterols were esterified to sunflower oil and the degree of
esterification was 82 percent. Blood total and LDL cholesterol levels
were reduced compared to the control spread (p 0.001) after 3.5 weeks.
Blood total cholesterol decreased by 4.9, 5.9, and 6.8 percent for
daily consumption of 1.33, 2.58, and 5.18 g/d plant sterol esters,
respectively. For LDL cholesterol these decreases were 6.7, 8.5, and
9.9 percent. No significant differences in cholesterol-lowering effect
between the three levels of plant sterol esters could be detected.
There were no effects on HDL cholesterol. The subjects' body weight
differed after daily consumption of 2.58 and 5.18 g plant sterol esters
by 0.3 kilogram (kg) (p 0.01), but this small difference in body
weight probably did not affect the study findings.
Another study by Jones et al. (Ref. 74) investigated the effects of
a mixture of plant sterols and plant stanols. The plant stanol compound
sitostanol made up about 20 percent of the mixture by weight. The
remaining sterol component of the mixture was composed mostly of the
plant sterols sitosterol and campesterol from tall oil (derived from
pine wood). The investigators evaluated the cholesterol-lowering
properties of this nonesterified plant sterol/stanol mixture in a
controlled feeding regimen based on a ``prudent,'' fixed-food North
American diet formulated to meet Canadian recommended nutrient intakes.
Thirty-two hypercholesterolemic men were fed either a diet of prepared
foods alone or the same diet plus 1.7 g per d of the plant sterol/
stanol mixture (in 30 g/d of margarine, consumed during 3 meals) for 30
days in a parallel study design. The plant sterol/stanol mixture had no
statistically significant effect on plasma total cholesterol
concentrations. However, LDL cholesterol concentrations on day 30 had
decreased by 8.9 percent (p 0.01) and 24.4 percent (p 0.001) with the
control and plant sterol/stanol-enriched diets, respectively. On day
30, LDL cholesterol concentrations were significantly lower (p 0.05)
by 15.5 percent in the group consuming the plant sterol/stanol mixture
compared to the control group. HDL cholesterol concentrations did not
change significantly during the study.
Weststrate and Meijer (Ref. 67) evaluated the effects of different
plant sterols on plasma total and LDL cholesterol in
normocholesterolemic and mildly hypercholesterolemic subjects consuming
their usual diets with the addition of a test or placebo margarine. A
randomized double-blind placebo-controlled balanced incomplete Latin
square design with five treatments and four periods of 3.5 weeks was
utilized to compare the effect of margarines (30 g/d) with added sterol
esters from soybean oil (4.8 g/d; 3 g/d free plant sterol), sheanut oil
(2.9 g/d) or ricebran oil (1.6 g/d) or with plant stanol esters (4.6 g/
d; 2.7 g/d free plant stanols) to a placebo margarine. The sterol
esters from soybean oil were mainly esters from sitosterol,
campesterol, and stigmasterol. Plasma total and LDL cholesterol
concentrations were significantly reduced, by 8.3 and 13.0 percent (p
0.05), respectively, compared to control, in the soybean oil sterol
ester margarine group. Similar reductions were reported in the plant
stanol ester margarine group (see discussion of this study in section
III. C.2.b of this document). Sterols from sheanut oil and rice bran
oil did not have a significant effect on cholesterol levels. No effects
on HDL cholesterol concentrations were reported in either the control
or any of the test groups. The cholesterol-lowering effects of
ingestion of plant sterol/stanol esters on blood cholesterol did not
differ between normocholesterolemic and mildly hypercholesterolemic
subjects. The authors concluded that both the margarine with plant
stanol esters and the margarine with sterol esters from soybean oil
were effective in lowering blood total and LDL cholesterol levels
without affecting HDL cholesterol concentrations. The authors further
suggested that incorporating such substances in edible fat-containing
products may substantially reduce the risk of cardiovascular disease in
the population.
Two reports of apparently the same study (Refs. 63 and 64) gave
inconclusive results regarding the relationship between plant sterol
consumption and blood cholesterol levels. Interpretation of this study
is complicated by design issues such as concerns about sample size and
level of plant sterol administered, but both reports are discussed here
and summarized in table 1 of this document because they provide
information to assist in determining the minimum level of plant sterol
esters necessary to provide a health benefit.
Miettinen and Vanhanen (Refs. 63 and 64 (1 study)) reported the
effect of small amounts of sitosterol (700 mg/d free sterols) and
sitostanol (700 mg/d free stanols) dissolved in 50 g rapeseed oil (RSO)
mayonnaise on serum cholesterol in 31 subjects with
hypercholesterolemia for 9 weeks. Subjects did not change their diets
except for replacing 50 g/d of dietary fat with the 50 g/d of RSO
mayonnaise. It appears that these authors later conducted another 9-
week phase of the study using sitostanol esters (1.36 g/d plant stanol
esters or 800 mg/d free stanols) dissolved in 50 g RSO mayonnaise. The
results of this later phase were reported in the Miettinen reference
(Ref. 63), together with the earlier results. The Vanhanen reference
(Ref. 64) reports only the earlier results for sitosterol and
sitostanol. The Vanhanen reference (Ref. 64) reports reduced serum
total cholesterol concentrations (8.5 percent) during the RSO
mayonnaise run-in period (stabilization period before the intervention
begins) compared to values before the run-in period when combining all
subjects. Continuation of RSO mayonnaise in the RSO mayonnaise control
group (n=8) during the experimental period had no further effect on
blood cholesterol (Refs. 63 and 64). (``N'' refers to the number of
subjects.) Neither sitosterol (n=9) nor sitostanol (n=7) significantly
altered serum total cholesterol or LDL cholesterol concentrations
compared to the RSO control group (n=8) during the experimental period
(Refs. 63 and 64). Sitostanol ester (n=7), however, significantly
reduced serum total and LDL cholesterol levels compared to the RSO
control group (Ref. 63). Furthermore, serum total cholesterol was
significantly reduced by 4 percent (p 0.05) during the experimental
period in an analysis, which compared the combined plant sterol/stanol
groups (sitostanol, sitosterol, and sitostanol ester groups; n=23) to
the RSO control group (n=8) (Ref. 63). HDL cholesterol did not change
in the plant sterol group compared to the RSO control group (Ref. 63).
The agency notes that it is difficult to decipher from the
descriptions in these
[[Page 54694]]
reports the amount of plant sterol that was consumed and the level of
cholesterol-lowering that was observed. For the sitosterol group, as an
example, the method section states that 722 mg/d of sitosterol was
added to the RSO mayonnaise, yet the abstract mentions that the RSO
mayonnaise contained an additional 625 mg/d of sitosterol (Ref. 64).
The results section of the Miettinen reference (Ref. 63) notes that in
the combined plant sterol/stanol groups, total and LDL cholesterol
levels were slightly but significantly decreased up to 4 percent, yet
the abstract states that serum total cholesterol was reduced by about 5
percent in the combined plant sterol/stanol groups. Therefore, FDA
considers the results in these reports inconclusive because of
inconsistencies in the descriptions of methods and results.
(c) Normocholesterolemics: ``typical'' or ``usual'' diets. The
results of three studies (Refs. 51, 65, and 75) support a cholesterol-
lowering effect of plant sterols in subjects with normal cholesterol
values.
Ayesh et al. (Ref. 51), in a controlled feeding study, reported
significantly lower serum total cholesterol (18 percent, p 0.0001) and
LDL cholesterol (23 percent, p 0.0001) in subjects consuming 13.8 g/d
vegetable oil sterol esters (8.6 g/d free plant sterols delivered in 40
g of margarine each day consumed with breakfast and dinner under
supervision) for 21 days in males and 28 days in females, compared to
subjects consuming a control margarine. These results were calculated
as the difference from baseline to days 21 for male and 28 for female;
analysis of covariance was adjusted for gender. There was no
significant difference in effect on HDL cholesterol between control and
plant sterol groups.
In a double-blind crossover study, Sierksma et al. (Ref. 75) showed
that daily consumption of 25 g of a spread enriched with free soybean
oil sterols (0.8 g/d) for 3 weeks lowered plasma total and LDL
cholesterol concentrations respectively by 3.8 percent (p 0.05) and 6
percent (p 0.05) compared with a placebo spread. No effect on plasma
HDL cholesterol was found. Subjects followed their usual diets, except
that they replaced their usual spread with the test or placebo spread.
The investigators also tested sheanut-oil sterols (3.3 g/d) in 25 g of
spread and found that the sheanut-oil spread did not lower plasma total
and LDL cholesterol levels. The sheanut-oil sterols were primarily
phenolic acid esters of 4,4-dimethyl sterols, whereas the soybean-oil
product contained 4-desmethyl sterols (the class of sterols containing
no methyl group at the carbon 4 atom). The structure of 4-desmethyl
sterols is more similar to cholesterol than the structure of 4,4-
dimethyl sterols. The investigators stated that soybean-oil sterol
structural similarity to cholesterol may offer increased competition
with cholesterol for incorporation in mixed micelles, the most likely
mechanism for the blood cholesterol-lowering action of plant sterols.
Pelletier et al. (Ref. 65) reported reductions in blood total
cholesterol (10 percent, p 0.001) and LDL cholesterol (15 percent, p
0.001), compared to a control period, in subjects consuming 740 mg/d of
soybean oil sterols (nonesterified) in 50 g/d of butter for 4 weeks.
These results were obtained in a crossover experiment in 12
normocholesterolemic men consuming a controlled, but ``normal'' diet.
The total fat intake as a percent of energy was 36.4 percent during
both the control and the plant sterol-feeding period. The cholesterol
intake during the control period was 436 mg/d; it was 410 mg/d during
the plant sterol-feeding period. The diets were designed to have a
plant sterol to cholesterol ratio of 2.0, which has repeatedly been
shown to affect cholesterol levels in various animal models. There was
no significant difference in effect on HDL cholesterol between control
and plant sterol groups.
(d) Other studies: research synthesis study. FDA considered the
results of a March 25, 2000, research synthesis study by Law (Ref. 100)
of the effect of plant sterols and stanols on serum cholesterol
concentrations. While evaluation of research synthesis studies,
including meta-analyses, is of interest, the appropriateness of such
analytical techniques in establishing substance/disease relationships
has not been determined. There are ongoing efforts to identify criteria
and critical factors to consider in both conducting and using such
analyses, but standardization of this methodology is still emerging.
Therefore, this research synthesis study was considered as supporting
evidence but did not weigh heavily within the body of evidence on the
relationship between plant sterol/stanol esters and CHD.
Law performed a research synthesis analysis of the effect of plant
sterols and stanols on serum cholesterol concentrations by pooling data
from randomized trials identified by a Medline search using the term
``plant sterols.'' Law obtained additional data for analysis from other
studies cited in papers and review articles. A total of 14 studies that
employed either a parallel or crossover design were incorporated in the
analysis, consisting of 20 dose comparisons of either plant sterols or
plant stanols to a control vehicle. The data described the effects on
serum LDL cholesterol concentrations obtained from using spreads (or in
some cases, mayonnaise, olive oil, or butter) with and without added
plant sterols or stanols. Studies that included children with familial
hypercholesterolemia were excluded from the research synthesis
analysis. Law included in the research synthesis analysis study
populations with severe hypercholesterolemia (mean serum total
cholesterol greater than 300 mg/dL) and study populations with previous
myocardial infarction or noninsulin dependent diabetes mellitus, as
well as study populations with mildly and moderately
hypercholesterolemic and/or normal cholesterol concentrations.
Based on the placebo-adjusted reduction in serum LDL cholesterol,
the analysis indicated that 2 g of plant sterol (equivalent to 3.2 g/d
of plant sterol esters) or plant stanol (equivalent to 3.4 g/d of plant
stanol esters) added to a daily intake of spread (or mayonnaise, olive
oil, or butter) reduces serum concentrations of LDL cholesterol by an
average of 20.9 mg/dL (0.54 millimole per liter (mmol/l)) in people
aged 50 to 59 (p=0.005), 16.6 mg/dL (0.43 mmol/l) in those aged 40 to
49 (p=0.005), and 12.8 mg/dL (0.33 mmol/l) in those aged 30 to 39
(p=0.005). The results indicated that the reduction in the
concentration of LDL cholesterol at each dose is significantly greater
in older people versus younger people. The reductions in blood total
cholesterol concentrations were similar to the LDL cholesterol
reductions and there was little change in serum concentrations of HDL
cholesterol. The results of this analysis also suggested that doses
greater than about 2 g of plant sterol (3.2 g/d of plant sterol esters)
or stanol (3.4 g/d of plant stanol esters) per day would not result in
further reduction in LDL cholesterol (Ref. 100).
Observational studies and randomized trials concerning the
relationship between serum cholesterol and the risk of heart disease
(Ref. 101) indicate that for people aged 50 to 59, a reduction in LDL
cholesterol of about 19.4 mg/dL (0.5 mmol/l) translates into a 25
percent reduction in the risk of heart disease after about 2 years.
Studies administering plant sterols and stanols have demonstrated the
potential to provide this protection. According to Law, the
cholesterol-lowering capacity of plant sterols and stanols is even
larger than the effect that could be expected to occur if people ate
less animal fat (or saturated fat) (Ref. 100).
[[Page 54695]]
(e) Summary. In one preliminary report of hypercholesterolemic
subjects consuming a low saturated fat and low cholesterol diet (Refs.
61 and 62 (1 study)), plant sterol ester intake was associated with
statistically significant decreases in serum total and LDL cholesterol
levels. Levels of HDL cholesterol did not change during plant sterol
consumption compared to controls. Levels of plant sterol ester found to
be effective in lowering serum total and LDL cholesterol levels, in the
context of a diet low in saturated fat and cholesterol, were reported
to be 1.76 and 3.52 g/d (1.1 and 2.2 g/d of free plant sterol) (Refs.
61 and 62 (1 study)).
In four (Refs. 57, 58, 67, and 74) of five (Refs. 57, 58, 67, 74,
and 63 and 64 (1 study)) studies of hypercholesterolemic subjects
consuming ``usual'' diets that were generally high in total fat,
saturated fat and cholesterol, plant sterol intake was associated with
statistically significant decreases in blood total and/or LDL
cholesterol levels. Levels of HDL cholesterol were found to be
unchanged by consumption of diets containing plant sterol (Refs. 57,
58, 67, 74, and 63 and 64 (1 study)). Levels of plant sterol ester
found to be effective in lowering blood total and/or LDL cholesterol
levels, in the context of a usual diet, ranged in these studies from
1.33 (Ref. 57) to 5.18 g/d (Ref. 57) (equivalent to 0.83 to 3.24 g/d of
free plant sterol).
The results of one study in hypercholesterolemic subjects consuming
``usual'' diets (Refs. 63 and 64 (1 study)) are inconclusive; this may
be due to lack of statistical power (e.g., sample size too small to
detect the hypothesized difference between groups) or too low a dose of
plant sterols to provide an effect. As previously discussed, the
descriptions of methods and results also were inconsistent and
difficult to interpret. These investigators report no effect of 700 mg/
d of plant sterol (equivalent to 1.12 g/d of plant sterol esters) on
blood cholesterol levels. However, when the results of three test
groups (700 mg/d plant sterol, 700 mg/d plant stanol, 1.36 mg/d plant
stanol ester) were pooled and compared to a control group, a
statistically significant effect on reducing serum total cholesterol
emerged, perhaps because the increased number of subjects in this
pooled analysis artificially increased the ability to detect a
difference.
In three of three studies (Refs. 51, 65, and 75) of healthy adults
with normal blood cholesterol levels consuming a ``usual'' diet, plant
sterol intake was associated with statistically significant decreases
in both blood total and LDL cholesterol levels. HDL cholesterol levels
were not significantly affected by plant sterol intake. Levels of plant
sterol found to be effective in lowering blood total and LDL
cholesterol ranged in these studies from 0.74 (Ref. 65) to 8.6 g/d
(equivalent to 1.2 to 13.8 g/d of plant sterol esters) (Ref. 51).
Based on these studies, FDA finds there is scientific evidence for
a consistent, clinically significant effect of plant sterol esters on
blood total and LDL cholesterol. The cholesterol-lowering effect of
plant sterol esters is consistent in both mildly and moderately
hypercholesterolemic populations and in populations with normal
cholesterol concentrations. The cholesterol-lowering effect of plant
sterol esters has been reported in addition to the effects of a low
saturated fat and low cholesterol diet. It has been consistently
reported that plant sterols do not affect HDL cholesterol levels. These
conclusions are drawn from the review of the well controlled clinical
studies and are supported by the research synthesis study of Law (Ref.
100).
2. Studies Evaluating the Effects of Plant Stanol Esters on Blood
Cholesterol
As discussed in section III.B.1.b of this document, FDA reviewed 24
studies (Refs. 58, 63 and 64 (1 study), 67, 74, 77 through 80, 81 and
82 (1 study), and 83 through 97) on plant stanols, including both free
and esterified forms. Of these, 15 met the selection criteria listed in
section III.B.2. of this document (Refs. 58, 63 and 64 (1 study), 67,
74, 77, 78, 80, 81 and 82 (1 study), 88 through 92, 94, and 97). These
studies are summarized in table 2 at the end of this document and
discussed below. The nine remaining studies (Refs. 79, 83 through 87,
93, 95, and 96) failed to meet the selection criteria because of
insufficient information to evaluate the design and method of the study
or because the populations studied were not considered representative
of the general U.S. adult population. For example, some of the studies
were performed in children with type II or familial
hypercholesterolemia; others used adult subjects with mean serum total
cholesterol levels > 300 mg/dL or subjects with preexisting disease
(e.g., diabetes). As supporting evidence, the results of a community
intervention study (Ref. 102) and a research synthesis study (Ref. 100)
that included a number of the plant stanol ester studies submitted in
the petition are discussed in section III.C.2.d of this document.
Studies typically report the amount of free plant stanol consumed,
rather than the levels of stanol esters administered. Where possible,
we report both the amount of plant stanol ester and the equivalent free
stanol.
(a) Hypercholesterolemics (serum cholesterol 300 mg/dL): low
saturated fat and cholesterol diets. Two studies (Refs. 77 and 80)
showed a relationship between consumption of plant stanol esters and
reduced blood cholesterol in hypercholesterolemic subjects who consumed
plant stanol esters as part of a low saturated fat and low cholesterol
diet.
Andersson et al. (Ref. 80) randomized subjects to receive one of
three test diets: Either a low fat margarine containing 3.4 g/d plant
stanol esters (2 g/d of plant stanols) with a controlled, low saturated
fat, low cholesterol diet; a control low fat margarine containing no
plant stanol esters with a controlled, low saturated fat, low
cholesterol diet; or to continue their normal diet with the addition of
the margarine containing 3.4 g/d plant stanol esters (2 g/d of plant
stanols). Serum total and LDL cholesterol were reduced in all three
groups after 8 weeks. The group consuming the margarine containing
plant stanol esters with the low saturated fat, low cholesterol diet
showed 12 percent (p 0.0035) and 15 percent (p 0.0158) reductions in
serum total and LDL cholesterol levels, respectively, compared to the
group that consumed a control low fat margarine with a controlled, low
saturated fat, low cholesterol diet. The serum total and LDL
cholesterol reductions were reported to be 4 percent (p 0.0059) and 6
percent (p 0.0034), respectively, for the group consuming the
margarine containing plant stanol esters with the low saturated fat,
low cholesterol diet compared to the group consuming the margarine
containing plant stanol esters with a normal diet. Although a normal
diet and control margarine group was not included, this study suggests
that 3.4 g/d of plant stanol esters in conjunction with a normal or
controlled, low saturated fat, low cholesterol diet can significantly
lower serum cholesterol levels. There was no change in HDL cholesterol
levels in the normal diet, plant stanol ester margarine group. The
study results suggest that the reduction in serum cholesterol levels is
significantly greater when the plant stanol esters are consumed as part
of a diet low in saturated fat and cholesterol. HDL cholesterol was
decreased, however, in subjects in both low saturated fat, low
cholesterol diet groups, and this result was statistically significant
in the group that consumed the plant stanol ester margarine in
conjunction with this diet.
[[Page 54696]]
Hallikainen et al. (Ref. 77) randomly assigned 55 mildly
hypercholesterolemic subjects, after a 4-week high fat diet (36 to 38
percent of energy from fat), to one of three low fat margarine groups:
a 3.9 g/d (2.31 g/d of free plant stanols) wood stanol ester-containing
margarine, a 3.9 g/d (2.16 g/d of free plant stanols) vegetable oil
stanol ester-containing margarine, or a control margarine group. The
groups consumed the margarines for 8 weeks as part of a diet resembling
that of the National Heart, Lung, and Blood Institute's National
Cholesterol Education Program Step II diet (a diet in which saturated
fat intake is less than 7 percent of calories and cholesterol is less
than 200 mg/d) (Ref. 99). During the experimental period, the serum
total cholesterol reduction was significantly greater in the wood
stanol ester-containing margarine (10.6 percent, p 0.001) and
vegetable oil stanol ester-containing margarine (8.1 percent, p 0.05)
groups than in the control group, but no significant differences were
found between the wood stanol ester-containing margarine and vegetable
oil stanol ester-containing margarine groups. The LDL cholesterol
reduction was significantly greater in the wood stanol ester-containing
margarine (13.7 percent p 0.01) group than in the control group. For
the vegetable oil stanol ester-containing margarine group, the LDL
cholesterol reduction was 8.6 percent greater than in the control, but
the difference was not statistically significant (p= 0.072). However,
there were no significant differences reported between the wood stanol
ester-containing margarine and vegetable oil stanol ester-containing
margarine groups for LDL cholesterol. HDL cholesterol concentrations
did not change during the study. The authors state, ``* * * that plant
stanols can reduce serum cholesterol concentrations, even in
conjunction with a markedly low dietary cholesterol intake, indicates
that plant stanols must inhibit not only the absorption of dietary
cholesterol but also that of biliary cholesterol.''
The results of another study (Ref. 97) did not show a relationship
between consumption of plant stanols and blood cholesterol in
hypercholesterolemic subjects who consumed plant stanols as part of a
low saturated fat and low cholesterol diet. In this study, Denke (Ref.
97) tested the cholesterol-lowering effects of dietary supplementation
with plant stanols (3 g/d suspended in safflower oil and packed into
gelatin capsules) in 33 men with moderate hypercholesterolemia who were
consuming a Step 1 diet. Plant stanol consumption did not significantly
lower plasma total cholesterol or LDL cholesterol compared with the
Step 1 diet alone. HDL cholesterol levels were also unchanged. The
authors state that although previous reports suggested that low dose
plant stanol consumption is an effective means of reducing plasma
cholesterol concentrations, its effectiveness may be attenuated when
the diet is low in cholesterol. The agency notes that, unlike several
of the studies submitted with the petition, this study was not a
randomized, placebo-controlled, double-blind study, but rather a fixed
sequence design. One result of this design was that during the plant
stanol dietary supplement phase the subjects consumed an additional 12
g of fat that they did not consume in other phases because each dietary
supplement contained 1g of safflower oil and subjects were instructed
to consume 4 capsules per meal (subjects were to consume a total of 12
capsules (3000 mg) in three divided doses during three meals). The
agency does not give as much weight to this study as it does the
studies in which subjects were randomly assigned to placebo or plant
stanol arms of a study with all else being equal among the
participants.
(b) Hypercholesterolemics (serum cholesterol 300 mg/dL):
``typical'' or ``usual'' diets. Eight studies (Refs. 63 and 64 (1
study), 67, 78, 81 and 82 (1 study), 88 through 90, and 94) show a
relationship between consumption of plant stanols and reduced blood
total and LDL cholesterol in hypercholesterolemic subjects consuming
diets within the range of a typical American diet. Two studies (Refs.
58 and 74) show a relationship between consumption of plant stanols and
reduced LDL cholesterol, but not blood total cholesterol, in the same
category of subjects consuming diets within the range of a typical
American diet.
Hallikainen et al. (Ref. 88) conducted a single-blind, crossover
study in which 22 hypercholesterolemic subjects consumed margarine
containing four different doses of plant stanol esters, including 1.4,
2.7, 4.1, and 5.4 g/d (0.8, 1.6, 2.4, and 3.2 g/d of free plant
stanols) for 4 weeks each. These test margarine phases were compared to
a control margarine phase, also 4 weeks long. All subjects followed the
same standardized diet throughout the study, and the order of the
margarine phases was randomized. Serum total cholesterol concentration
decreased (calculated in reference to control) by 2.8 percent for the
1.4 g/d dose (p=0.384), 6.8 percent for the 2.7 g/d dose (p 0.001),
10.3 percent for the 4.1 g/d dose (p0.001) and 11.3 percent (p 0.001)
for the 5.4 g/d dose of plant stanol esters. The respective decreases
for LDL cholesterol were 1.7 percent (p=0.892), 5.6 percent (p 0.05),
9.7 percent (p0.001) and 10.4 percent (p0.001). Although decreases were
numerically greater with 4.1 and 5.4 g doses than with the 2.7 g dose,
these differences were not statistically significant (p=0.054-0.516).
This study demonstrates that at least 2.7 g/d of plant stanol esters
can significantly reduce both serum total cholesterol and LDL
cholesterol levels by at least 5.6 percent compared to control. No
statistically significant changes in HDL cholesterol were observed with
any of the plant stanol ester margarines.
Gylling and Miettinen (Ref. 78) reported the serum cholesterol-
lowering effects of feeding different campestanol/sitostanol mixtures
in margarine or butter in 23 postmenopausal women using a double-blind
crossover design. The participants were randomly allocated to study
periods where they consumed 25 g/d of plant stanol-containing rapeseed
oil margarine with either 5.4 g sitostanol ester-rich (3.18 g of free
plant stanols; wood-derived plant stanol esters with a campestanol to
sitostanol ratio 1:11) plant stanol esters or 5.7 g campestanol ester-
rich (3.16 g of free plant stanols; vegetable oil-derived plant stanol
esters with a campestanol to sitostanol ratio 1:2) plant stanol esters.
After 6 weeks, subjects consumed the other margarine for an additional
6 weeks. Following an 8 week home diet wash-out period, 21 of the
subjects were randomly assigned to consume either 25 g of butter or 4.1
g/d plant stanol esters (2.43 g/d of free plant stanols with a
campestanol to sitostanol ratio 1:1) in 25 g of butter for an
additional 5 weeks. Throughout the study, subjects consumed their usual
diets, except that they were instructed to substitute the 25 g/d of
butter or margarine consumed as part of the study for 25 g of their
normal daily fat intake. Both the wood and vegetable stanol ester
margarines lowered serum total cholesterol by 4 and 6 percent,
respectively, compared to baseline (p 0.05 for both). LDL cholesterol
was reduced by 8 and 10 percent with the wood and vegetable stanol
ester margarines, respectively, versus baseline (p 0.05 for both).
Furthermore, HDL cholesterol was increased by 6 and 5 percent (p 0.05)
with the wood and vegetable stanol ester margarines, respectively,
versus baseline, so the LDL/HDL cholesterol ratio was reduced by 15
percent (p
[[Page 54697]]
0.05 for both). The two plant stanol mixtures in margarine appeared
equally effective in reducing serum cholesterol. Butter alone increased
serum total and LDL cholesterol by 4 percent (p 0.05 for total
cholesterol, not statistically significant for LDL cholesterol).
Although the plant stanol ester butter did not significantly reduce
serum total and LDL cholesterol compared to baseline, the plant stanol
ester butter was found to decrease serum total cholesterol by 8 percent
and LDL cholesterol by 12 percent (p 0.05 for both) compared to butter
alone. There was no significant change in HDL cholesterol between the
two butter groups. The study reported that plant stanol esters are able
to decrease serum total and LDL cholesterol in a saturated environment,
i.e., when plant stanol ester is consumed in butter, a high saturated-
fat food, and compared to the effects of butter without plant stanol
esters. The observation that the plant stanol ester butter did not
reduce blood cholesterol levels compared to baseline suggests that
plant stanol esters do not completely counteract the impact of a high
saturated-fat diet on blood cholesterol levels.
Nguyen et al. (Ref. 90) examined the blood cholesterol-lowering
effects in subjects consuming either a European spread containing 5.1
g/d plant stanol esters (3 g/d free plant stanols), a U.S.-reformulated
spread containing 5.1 g/d plant stanol esters (3 g/d free plant
stanols), a U.S.-reformulated spread containing 3.4 g/d plant stanol
esters (2 g/d of free plant stanols), or a U.S.-reformulated spread
without plant stanol esters for 8 weeks. The subjects consumed a total
of 24 g of spread in three 8 g servings a day, but made no other
dietary changes. Serum total cholesterol (p 0.001) and LDL cholesterol
(p 0.02) levels were significantly reduced in all three test groups
compared with the placebo group at all time points during the
ingredient phase. The U.S. spread containing 5.1 g/d plant stanol
esters lowered serum total and LDL cholesterol by 6.4 and 10.1 percent,
respectively, when compared to baseline (p 0.001). Subjects consuming
the 5.1 g/d plant stanol esters European spread achieved a 4.7 percent
reduction in serum total cholesterol and a 5.2 percent reduction in LDL
cholesterol compared to baseline (p 0.001). The 3.4 g/d plant stanol
ester U.S. spread group showed a 4.1 percent reduction in both serum
total and LDL cholesterol levels compared to baseline (p 0.001). HDL
cholesterol levels were unchanged throughout the study.
Weststrate and Meijer (Ref. 67) evaluated the effects of different
plant sterols and stanols on plasma total and LDL cholesterol in
normocholesterolemic and mildly hypercholesterolemic subjects. The
subjects consumed their usual diets with the addition of a test or
placebo margarine. A randomized double-blind placebo-controlled
balanced incomplete Latin square design with five treatments and four
periods of 3.5 weeks was utilized to compare the effect of margarines
(30 g/d) with added plant stanol esters (4.6 g/d; 2.7 g/d free plant
stanols), or with added plant sterol esters from sheanut oil (2.9 g/d),
ricebran oil (1.6 g/d), or soybean oil (4.8 g/d; 3 g/d free plant
sterol) to a placebo margarine. Plasma total and LDL cholesterol
concentrations were significantly reduced by 7.3 and 13.0 percent (p
0.05), respectively, compared to control, in the plant stanol ester
margarine group. Similar reductions were reported in the soybean oil
sterol ester margarine group (see discussion of this study in section
III.C.1.b of this document). No effect on HDL cholesterol
concentrations was reported during the study.
In a long term study conducted in Finland (Ref. 89), 153 mildly
hypercholesterolemic subjects were instructed to consume 24 g/d of
canola oil margarine or the same margarine with added plant stanol
esters for a targeted consumption of 5.1 g/d plant stanol esters (3 g/d
free plant stanols), without other dietary changes. At the end of 6
months, those consuming plant stanol esters were randomly assigned
either to continue the test margarine with a targeted intake of 5.1 g/d
plant stanol esters or to switch to a targeted intake of 3.4 g/d plant
stanol esters (2 g/d free plant stanols) for an additional 6 months.
The control group also continued for another 6 months. Based on
measured margarine consumption, average plant stanol ester intakes were
4.4 g/d (in the 5.1 g/d target group) and 3.1 g/d (in the 3.4 g/d
target group). The mean 1 year reduction in serum total cholesterol was
10.2 percent in the 4.4 g/d plant stanol ester group, as compared with
an increase of 0.1 percent in the control group. The difference in the
change in serum total cholesterol concentration between the two groups
was -24 mg/dL (p 0.01). The respective reductions in LDL cholesterol
were 14.1 percent in the 4.4 g/d plant stanol ester group and 1.1
percent in the control group. The differences in the change in LDL
cholesterol concentration between the two groups was -21 mg/dL (p
0.001). Significant reductions in serum total and LDL cholesterol were
also reported after consuming plant stanol esters for 6 months. Unlike
the group consuming 4.4 g/d of plant stanol esters for 12 months, where
continued reductions in serum total and LDL cholesterol were observed
from 6 to 12 months, the reduction in plant stanol ester intake to 3.1
g/d at 6 months was not followed by any further decrease in the serum
total and LDL cholesterol concentrations. Serum HDL cholesterol
concentrations were not affected by plant stanol esters.
Vanhanen et al. (Ref. 94) reported the hypocholesterolemic effects
of 1.36 g/d of plant stanol esters (800 mg/d of free plant stanols) in
RSO mayonnaise for 9 weeks followed by 6 weeks of consumption of 3.4 g/
d of plant stanol esters (2 g/d of free plant stanols) in RSO
mayonnaise compared to a group receiving RSO mayonnaise alone. Subjects
consumed their usual diets, except that they were instructed to
substitute the RSO mayonnaise for 50 g/d of their normal daily fat
intake. After 9 weeks of consumption of the lower dose plant stanol
ester mayonnaise, the changes in serum levels of total and LDL
cholesterol were -4.1 percent (p 0.05) and -10.3 percent (not
statistically significant), respectively, as compared to the control.
Greater reductions in both serum total and LDL cholesterol were
observed after consumption of 3.4 g/d of plant stanol esters for an
additional 6 weeks (p 0.05). The changes in serum levels of total and
LDL cholesterol were -9.3 percent and -15.2 percent, respectively, for
subjects consuming 3.4 g/d of plant stanol esters as compared to
control. Plant stanol ester consumption in RSO mayonnaise did not
change HDL cholesterol levels compared to control RSO mayonnaise.
Blomqvist et al. (Ref. 81) and Vanhanen et al. (Ref. 82) separately
reported the results of another study showing plasma cholesterol-
lowering effects of plant stanol esters dissolved in RSO mayonnaise.
After subjects replaced 50 g of their daily fat intake by 50 g of RSO
mayonnaise for 4 weeks, they were randomized into two groups, one that
continued with the original RSO mayonnaise (control group) and the
other with RSO mayonnaise in which 5.8 g of plant stanol ester was
dissolved (3.4 g/d of free plant stanols in 50 g of mayonnaise
preparation). After 6 weeks on the plant stanol ester-enriched diet,
plasma total and LDL cholesterol were reduced from 225 <plus-minus> 27
(control group) to 2- <plus-minus> 34 mg/dL (plant stanol ester group)
(p 0.001) and from 134 <plus-minus> 18 (control group) to 124
<plus-minus> 32 mg/dL (plant stanol ester) (p 0.01), respectively (Ref.
81). In the report by
[[Page 54698]]
Blomqvist (Ref. 81), HDL cholesterol was reported to be significantly
lower in the plant stanol ester group compared to the control group.
Using the same data, with the exception that the number of control
subjects utilized in the analysis was 33 rather than 32 as in the
Blomqvist report, HDL cholesterol was reported to be unchanged in the
report by Vanhanen (Ref. 82). The agency does not give as much weight
to this study because the two reports lacked sufficient detail on the
reason for the varying number of control subjects.
Two reports of apparently the same study (Refs. 63 and 64) gave
inconclusive results regarding the relationship between plant stanol
ester consumption and blood cholesterol levels. Interpretation of this
study is complicated by design issues such as concerns about sample
size and level of plant sterol/stanol administered, but both reports
are discussed here and summarized in table 2 of this document because
they provide information to assist in determining the minimum level of
plant stanol esters necessary to provide a health benefit.
Miettinen and Vanhanen (Refs. 63 and 64 (1 study)) reported the
effect of small amounts of sitosterol (700 mg/d free sterols) and
sitostanol (700 mg/d free stanols) dissolved in 50 g RSO mayonnaise on
serum cholesterol in 31 subjects with hypercholesterolemia for 9 weeks.
Subjects did not change their diets except for replacing 50 g/d of
dietary fat with the 50 g/d of RSO mayonnaise. It appears that these
authors later conducted another 9-week phase of the study using
sitostanol esters (1.36 g/d plant stanol esters or 800 mg/d free
stanols) dissolved in 50 g RSO mayonnaise. The results of this later
phase were reported in the Miettinen reference (Ref. 63), together with
the earlier results. The Vanhanen reference (Ref. 64) reports only the
earlier results for sitosterol and sitostanol. The Vanhanen reference
(Ref. 64) reports reduced serum total cholesterol (8.5 percent)
concentrations during the RSO mayonnaise run-in period compared to
values before the run-in period when combining all subjects.
Continuation of RSO mayonnaise in the RSO mayonnaise control group
(n=8) during the experimental period had no further effect on blood
cholesterol (Refs. 63 and 64). Free sitostanol (n=7) did not
significantly alter serum total cholesterol or LDL cholesterol compared
to the RSO control group during the experimental period (Refs. 63 and
64). HDL cholesterol also did not change in the free sitostanol group
(Ref. 63). Serum total and LDL cholesterol were significantly reduced
in the sitostanol ester group (n=7), however (Ref. 63). The mean change
in serum total cholesterol from baseline was -7.4 mg/dL in the
sitostanol ester group, compared to +4.6 mg/dL in the control group (p
0.05). The mean change in LDL cholesterol from baseline was -7.7 mg/dL
in the sitostanol ester group compared to +3.1 mg/dL in the control
group (p 0.05). A statistically significant increase in HDL
cholesterol from baseline, however, was reported in the sitostanol
ester-treated group (Ref. 63).
The agency notes that it is difficult to decipher from the
descriptions in these reports the amount of plant stanol ester that was
consumed and the level of cholesterol-lowering that was observed. For
the sitostanol ester group, as an example, the experimental design
section states that 800 mg/d of sitostanol transesterified with RSO
fatty acids was added to the RSO mayonnaise, yet table 1 of this
document shows that the amount of sitostanol ester in the RSO
mayonnaise was 830 mg (Ref. 63). Since the conversion factor to obtain
the stanol ester equivalent of a given amount of free stanol is 1.7,
the amounts of sitostanol and sitostanol ester given in the
experimental design section and table 1 cannot both be correct. Based
on information in the results section of the Miettinen reference (Ref.
63), serum total cholesterol reduction in the sitostanol ester group
can be calculated to be approximately 18 percent as compared to
control, yet the abstract of the Vanhanen reference mentions that
sitostanol ester reduced serum total cholesterol by 7 percent (Ref.
63). Therefore, FDA considers the results in these reports inconclusive
because of inconsistencies in the descriptions of methods and results.
Two studies (Refs. 58 and 74) show a relationship between
consumption of plant stanols and reduced LDL cholesterol, but not blood
total cholesterol, in subjects consuming a diet within the range of a
typical American diet, although the diet was a controlled feeding
regimen formulated to meet Canadian recommended nutrient intakes.
Jones et al. (Ref. 58) reported the effects of consuming 2.94 g/d
of plant sterol esters in 23 g of margarine, 3.31 g/d of plant stanol
esters in 23 g of margarine (1.84 g/d free plant stanols; daily
margarine doses were divided into three equal portions and added to
each meal) and 23 g/d of control margarine for 21 days each, using a
controlled feeding crossover study design. During the experimental
period, subjects consumed a fixed-food North American diet formulated
to meet Canadian recommended nutrient intakes. The results from
consumption of the plant sterol ester margarine are discussed in
section III.C.1.b of this document. Plasma LDL cholesterol levels were
reduced by 6.4 percent (p 0.02) in the plant stanol ester group
compared to the control group. Plasma total cholesterol was not
significantly reduced in the plant stanol ester group. Plasma HDL
cholesterol did not differ across groups, and there was no significant
weight change shown by the subjects while consuming any of the
margarine mixtures.
Jones et al. (Ref. 74) evaluated the effects of a mixture of plant
stanols and plant sterols. The plant stanol compound sitostanol made up
about 20 percent of the mixture by weight. The remaining sterol
component of the mixture was mostly composed of the plant sterols
sitosterol and campesterol. These investigators evaluated the
cholesterol-lowering properties of this nonesterified plant sterol/
stanol mixture in a controlled feeding regimen based on a ``prudent,''
fixed-food North American diet formulated to meet Canadian recommended
nutrient intakes. Thirty-two hypercholesterolemic men were fed either a
diet of prepared foods alone or the same diet plus 1.7 g/d of the plant
sterol/stanol mixture (in 30 g/d of margarine, consumed during 3 meals)
for 30 days in a parallel study design. The plant sterol/stanol mixture
had no statistically significant effect on plasma total cholesterol
concentrations. However, LDL cholesterol concentrations on day 30 had
decreased by 8.9 percent (p 0.01) and 24.4 percent (p 0.001) with the
control and plant sterol/stanol-enriched diets, respectively. On day
30, LDL cholesterol concentrations were significantly lower (p 0.05)
by 15.5 percent in the group consuming the plant sterol/stanol mixture
compared to the control group. HDL cholesterol concentrations did not
change significantly during the study.
(c) Normocholesterolemics: ``typical'' or ``usual'' diets. Two
studies (Refs. 91 and 92) show a relationship between consumption of
plant stanols and reduced blood cholesterol in subjects with normal
cholesterol concentrations consuming a typical American diet.
Plat and Mensink (Ref. 92) examined the effects of two plant stanol
ester preparations in healthy subjects with normal serum cholesterol
levels. During a 4 week run-in period, 112 subjects consumed a rapeseed
oil margarine (20 g/d) and shortening (10 g/d). For the next 8 weeks,
42 subjects continued with these products, while the other
[[Page 54699]]
subjects received margarine (20 g/d) and shortening (10 g/d) with a
vegetable oil-based stanol ester mixture (6.8 g/d plant stanol esters
or 3.8 g/d free plant stanols) or pine wood-based stanol ester mixture
(6.8 g/d plant stanol ester or 4 g/d plant stanol). Subjects did not
change their diets except for replacing 30 g/d of dietary fat with the
30 g/d of test margarine and shortening. In the vegetable oil plant
stanol ester group, the mean change in serum total cholesterol from
baseline was -16.6 mg/dL, compared to -1.6 mg/dL in the control group
(p 0.001). In the pine wood stanol ester group, the mean change in
serum total cholesterol from baseline was -16.3 mg/dL compared to -1.6
mg/dL in the control group (p 0.001). Compared to consumption of a
control margarine and shortening, consumption of 6.8 g/d of vegetable
oil-based stanol esters lowered LDL cholesterol by 14.6 <plus-minus>
8.0 percent (p 0.001). Consumption of 6.8 g/d of the pine wood-based
stanol esters showed a comparable decrease of 12.8 <plus-minus> 11.2
percent (p 0.001) in comparison to control margarine consumption.
Decreases in LDL cholesterol were not significantly different between
the two experimental groups (p= 0.793). Serum HDL cholesterol did not
change during the study.
Niinikoski et al. (Ref. 91) randomly assigned 24 subjects with
normal serum cholesterol levels to use either a plant stanol ester
margarine (5.1 g/d plant stanol esters; 3 g/d of free plant stanols) or
ordinary rapeseed oil margarine (control) for 5 weeks. Subjects
followed their normal diets, except for substituting the test or
control margarine for normal dietary fat intake. During the study
period the mean plus/minus standard deviation for serum total
cholesterol decreased more in the plant stanol ester spread group (-31
plus/minus 19.4) compared to the ordinary rapeseed oil spread group (-
11.6 plus/minus 19.4) (p 0.05). Serum non-HDL (LDL plus very low
density lipoprotein) cholesterol also decreased more in the plant
stanol ester group (-31 plus/minus 23) compared to the control group (-
11.6 plus/minus 19.4) (p 0.05), but the plant stanol ester spread did
not influence HDL cholesterol concentration (p= 0.71 between groups).
(d) Other studies: research synthesis study. As discussed in
section III.C.1.d of this document, the agency considered the results
of a March 25, 2000, research synthesis study (Ref. 100) of the effect
of plant sterols and plant stanols on serum cholesterol concentrations
as supporting evidence on the relationship between plant sterol/stanol
esters and CHD. In this research synthesis study, the combined effect
of plant sterols and stanols on serum cholesterol concentrations was
analyzed by pooling data from 14 randomized trials that employed either
a parallel or crossover design, consisting of 20 dose comparisons of
either plant sterols or plant stanols to a control vehicle. The data
described the effects on serum LDL cholesterol concentrations obtained
from using spreads (or, in some cases, mayonnaise, olive oil, or
butter) with and without added plant sterols or stanols.
Based on the placebo-adjusted reduction in serum LDL cholesterol,
the analysis indicated that 2 g of plant sterol (equivalent to 3.2 g/d
of plant sterol esters) or plant stanol (equivalent to 3.4 g/d of plant
stanol esters) added to a daily intake of spread (or mayonnaise, olive
oil, or butter) reduces serum concentrations of LDL cholesterol by an
average of 20.9 mg/dL in people aged 50 to 59 (p=0.005), 16.6 mg/dL in
those aged 40 to 49 (p=0.005), and 12.8 mg/dL in those aged 30 to 39
(p=0.005). The results indicated that the reduction in the
concentration of LDL cholesterol at each dose is significantly greater
in older people versus younger people. Reductions in blood total
cholesterol concentrations were similar to the LDL cholesterol
reductions and there was little change in serum concentrations of HDL
cholesterol. The results of this analysis also suggested that doses
greater than about 2 g of plant sterol (3.2 g/d of plant sterol esters)
or stanol (3.4 g/d of plant stanol esters) per day would not result in
further reduction in LDL cholesterol.
Observational studies and randomized trials concerning the
relationship between serum cholesterol and the risk of heart disease
(Ref. 101) indicate that for people aged 50 to 59, a reduction in LDL
cholesterol of about 19.4 mg/dL (0.5 mmol/l) translates into a 25
percent reduction in the risk of heart disease after about 2 years.
Studies administering plant sterols and stanols have demonstrated the
potential to provide this protection. According to Law, the
cholesterol-lowering capacity of plant sterols and stanols is even
larger than the effect that could be expected to occur if people ate
less animal fat (or saturated fat) (Ref. 100).
Community Intervention Study
The plant stanol ester petitioner also submitted a community
intervention study by Puska et al. (Ref. 102) that described the
relationship between consumption of plant stanol ester-containing
margarine and serum total cholesterol concentrations in North Karelia,
Finland. FDA considered this study as supporting evidence for the
relationship between plant stanol esters and CHD. In the early 1970's,
Finland had the highest cardiovascular-related mortality in the world.
Since 1972, active prevention programs carried out in the framework of
the North Karelia Project have reduced these high rates. A central
target of these programs was promotion of dietary changes to reduce
population cholesterol levels. In spite of great success in the 1970's
and 1980's, cholesterol levels at the end of the 1980's remained, by
international standards, relatively high in North Karelia, especially
in rural areas. The Village Cholesterol Competition was introduced as
an innovative method to promote further cholesterol reduction in the
population. Puska et al. (Ref. 102) describe two competitions (1991 and
1997) in which serum cholesterol values of subjects ages 20 to 70 years
in participating villages were measured twice during a 2 month period.
The village with the greatest mean reduction in serum cholesterol was
awarded a monetary prize. The 1991 competition is not relevant to this
interim rule because plant stanol ester-containing spreads were not
available at the time. However, the 1997 competition is relevant
because plant stanol ester-containing spreads had become available and,
as discussed below, were consumed by a significant number of
participants. Subjects were asked to complete a questionnaire about
demographic factors, risk factors, dietary changes, and physical
activity. The questionnaire included specific questions on changes in
use of milk, fat spreads, fat used for baking, and food preparation.
Participating villages were responsible for arranging intervention
activities and blood cholesterol measurements.
Sixteen villages, with a total of 1,333 participants, were included
in the results. There were 8 weeks between the initial and final blood
cholesterol measurements. Approximately 24 percent of the participants
changed their fat spread on bread to recommended alternatives (e.g.,
from butter to margarine), but 57 percent did not make any changes in
their choice of spread. Use of plant stanol ester-containing spread
increased nearly fivefold, whereas use of butter, butter-vegetable oil
mixture and normal vegetable margarine use declined. Approximately 200
participants began to use plant stanol ester spread during the
competition as their fat spread on bread.
The winning village had an average serum total cholesterol
reduction of 16 percent (p 0.001). Results for each village were
calculated as the mean percent reduction in individual
[[Page 54700]]
cholesterol levels. The mean reduction in serum total cholesterol of
all participating villages was 9 percent (p 0.001). In 14 of 16
villages, the reduction between the initial and final blood cholesterol
measurements was statistically significant (p 0.05). The investigators
observed that the greater the self-reported daily use of the plant
stanol ester spread, the greater the serum cholesterol reduction.
Furthermore, of those who reported using more than 5 teaspoonfuls per
day of plant stanol ester-containing spread, an average serum total
cholesterol reduction of 21.3 percent was achieved.
(e) Summary. In two (Refs. 77 and 80) of three (Refs. 77, 80, and
97) studies of hypercholesterolemic subjects consuming low saturated
fat and low cholesterol diets, plant stanol ester intake was associated
with statistically significant decreases in total and LDL cholesterol
levels when compared to a control group. Levels of HDL cholesterol were
found to be unchanged (Refs. 77, 80, and 97).
Levels of plant stanol esters found to be effective in lowering
total and LDL cholesterol levels, in the context of a diet low in
saturated fat and cholesterol, were 3.4 g (Ref. 80) and 3.9 g (Ref. 77)
(equivalent to 2 and 2.31 g of free plant stanols, respectively). Other
results from one of these studies (Ref. 77) reported a statistically
significant effect of 3.9 g/d of vegetable oil stanol esters (2.16 g/d
of free plant stanols) on blood total cholesterol, but not LDL
cholesterol. Dietary supplementation with 3 g of plant stanols per day
(equivalent to 5.1 g/d of plant stanol esters) to hypercholesterolemic
subjects consuming a low saturated fat and low cholesterol diet (Ref.
97) did not significantly lower plasma total or LDL cholesterol.
In 10 of 10 studies of hypercholesterolemic subjects consuming
``usual'' diets (Refs. 58, 63 and 64 (1 study), 67, 74, 78, 81 and 82
(1 study), 88 through 90, and 94), plant stanol ester intake was
associated with statistically significant decreases in blood total and/
or LDL cholesterol levels. In seven (Refs. 58, 67, 74, 88 through 90,
and 94) of these ten studies, HDL cholesterol levels were not
significantly affected by plant stanol dietary treatment. In 2 studies
(Refs. 63 and 64 (1 study) and 78) of the 10 studies, plant stanol
esters were reported to increase the levels of HDL cholesterol from
baseline levels. Two separate published reports of another study (Refs.
81 and 82) were inconsistent in their description of effects on HDL
cholesterol. One publication (Ref. 81) reported HDL cholesterol to be
significantly lower in the plant stanol ester group compared to a
control group, but the other publication reported that the difference
in HDL cholesterol between the two groups was not significant (Ref.
82). This incongruity may be due to the difference in the number of
control subjects utilized in the analysis between the two publications.
The agency notes that the majority of studies do not report a
statistically significant change in HDL cholesterol in the plant stanol
ester groups compared to the control groups.
Levels of plant stanol esters found to be effective in lowering
total and/or LDL cholesterol levels in hypercholesterolemic subjects
consuming a ``usual'' diet ranged from 1.36 to 5.8 g/d (equivalent to
0.8 to 3.4 g/d of free plant stanols) (Refs. 58, 63 and 64 (1 study),
67, 74, 78, 81 and 82 (1 study), 88 through 90, and 94). In the study
by Hallikainen et al. (Ref. 88), 1.4 g/d plant stanol ester (0.8 g/d of
free plant stanol) did not significantly reduce serum cholesterol
levels, but intakes of 2.7, 4.1, and 5.4 g/d of plant stanol esters
(1.6, 2.4, and 3.2 g/d of free plant stanols, respectively) were found
to significantly reduce both serum total and LDL cholesterol levels. In
another of the 10 studies described above (Ref. 94), subjects consuming
a higher dose (3.4 g/d, equivalent to 2 g/d of free plant stanols) of
plant stanol esters showed statistically significant reductions in both
blood total and LDL cholesterol, but a lower dose of plant stanol
esters (1.36 g/d, equivalent to 0.8 g/d of free plant stanols) showed
reductions in blood total, but not in LDL cholesterol. The results of
the study by Miettinen and Vanhanen (Refs. 63 and 64) are inconclusive.
This may be due to lack of statistical power (e.g., sample size too
small to detect the hypothesized difference between groups) or too low
a dose of plant stanols to provide an effect. As previously discussed,
the descriptions of methods and results also were inconsistent and
difficult to interpret. Although these investigators reported (Ref. 63)
a statistically significant effect of 1.36 g/d plant stanol esters
(equivalent to 0.8 g/d of free plant stanols) on reducing serum total
and LDL cholesterol compared to a control group, there was no effect of
700 mg/d of the free plant stanols (equivalent to 1.19 g/d of plant
stanol esters) on blood cholesterol levels.
Two studies (Refs. 91 and 92) examined the effects of plant stanol
esters in healthy adults with normal cholesterol levels consuming a
``usual'' diet. Both of these studies demonstrated significant
decreases in blood total and LDL cholesterol or non-HDL cholesterol
levels when compared to controls. Levels of plant stanol esters found
to be effective were 6.8 g/d (vegetable oil stanol esters; 3.8 g/d of
free plant stanols) (Ref. 92), 6.8 g/d (pine wood stanol esters; 4 g/d
of free plant stanols) (Ref. 92), and 5.1 g/d (source unreported;
approximately 3 g/d of free plant stanols) (Ref. 91). HDL cholesterol
levels were not significantly affected by plant stanol consumption in
these reports.
Based on these studies, FDA finds there is scientific evidence for
a consistent, clinically significant effect of plant stanol esters on
blood total and LDL cholesterol. The cholesterol-lowering effect of
plant stanol esters is consistent in both mildly and moderately
hypercholesterolemic populations and in populations with normal
cholesterol concentrations. The cholesterol-lowering effect of plant
stanol esters has been reported in addition to the effects of a low
saturated fat and low cholesterol diet. Most studies also report that
plant stanols do not affect HDL cholesterol levels. These conclusions
are drawn from the review of the well controlled clinical studies and
are supported by the research synthesis study of Law (Ref. 100) and the
community intervention trial of Puska et al. (Ref. 102).
IV. Decision to Authorize a Health Claim Relating Plant Sterol/
Stanol Esters to Reduction in Risk of CHD
A. Relationship Between Plant Sterol Esters and CHD
The plant sterol esters petition provided information on pertinent
human studies that evaluated the effects on serum total cholesterol and
LDL cholesterol levels from dietary intervention with plant sterols or
plant sterol esters in subjects with normal to mildly or moderately
elevated serum cholesterol levels. FDA reviewed the information in the
petition as well as other pertinent studies identified by the agency's
literature search.
FDA concludes that, based on the totality of publicly available
scientific evidence, there is significant scientific agreement to
support a relationship between consumption of plant sterol esters and
the risk of CHD. The evidence that plant sterol esters affect the risk
of CHD is provided by studies that measured the effect of plant sterol
ester consumption on the two major risk factors for CHD, serum total
and LDL cholesterol.
In most intervention trials in subjects with mildly to moderately
elevated cholesterol levels (total cholesterol 300 mg/dL), plant sterol
esters were found to
[[Page 54701]]
reduce blood total and/or LDL cholesterol levels to a significant
degree (Refs. 57, 58, 61 and 62 (1 study), 67, and 74). Moreover, HDL
cholesterol levels were unchanged (Refs. 57, 58, 61 and 62 (1 study),
67, and 74). Results in normocholesterolemic subjects (Refs. 51, 65,
and 75) were similar to the results in mildly to moderately
hypercholesterolemic subjects.
Most of the studies in subjects with mildly to moderately elevated
cholesterol levels used ``usual'' diets in either a controlled feeding
(Refs. 58 and 74) or free-living (Refs. 57, 63 and 64 (1 study), and
67) situation, but one study used a low saturated fat, low cholesterol
diet during the study (Refs. 61 and 62 (1 study)). All three of the
studies in subjects with normal blood cholesterol levels used ``usual''
diets in either a controlled feeding (Refs. 51 and 65) or free-living
(Ref. 75) situation. Plant sterol esters have been reported to lower
blood cholesterol levels in subjects with mildly to moderately elevated
cholesterol consuming either a ``usual'' diet or low saturated fat, low
cholesterol diet and in subjects with normal blood cholesterol levels
consuming ``usual'' diets. Therefore, the evidence suggests that the
blood cholesterol-lowering response occurs regardless of the type of
background diet subjects consume.
Plant sterols (esterified or free) were tested in either a spread,
margarine, or butter carrier and produced fairly consistent results
regardless of the food carrier and apparent differences in processing
techniques. Given the variability of amounts and of food carriers in
which plant sterols and plant sterol esters were provided in the diets
studied, the response of blood cholesterol levels to plant sterols
appears to be consistent and substantial, except for plant sterols from
sheanut oil and ricebran oil (Refs. 67 and 75).
Based on the totality of the publicly available scientific
evidence, the agency concludes that there is significant scientific
agreement that plant sterol esters from certain sources will help
reduce serum cholesterol and that such reductions may reduce the risk
of CHD. Section 101.83(c)(2)(ii)(A)(1) (discussed in section V.C of
this document) specifies the plant sterol esters that have been
demonstrated to have a relationship to the risk of CHD. In the majority
of clinical studies evaluating plant sterols or plant sterol esters,
blood total and LDL cholesterol were the lipid fractions shown to be
the most affected by plant sterol intervention. As discussed in section
I of this document, reviews by Federal agencies and other scientific
bodies have concluded that there is substantial epidemiologic and
clinical evidence that high blood levels of total cholesterol and LDL
cholesterol represent major contributors to CHD and that dietary
factors that decrease blood total cholesterol and LDL cholesterol will
affect the risk of CHD (56 FR 60727 at 60728, and Refs. 18 through 21).
Given all of this evidence, the agency is authorizing a health
claim on the relationship between plant sterol esters and reduced risk
of CHD.
B. Relationship Between Plant Stanol Esters and CHD
The plant stanol esters petition provided information on pertinent
human studies that evaluated the effects on serum total cholesterol and
LDL cholesterol levels from dietary intervention with plant stanols or
plant stanol esters in subjects with normal to mildly or moderately
elevated serum cholesterol levels. FDA reviewed the information in the
plant stanol esters petition as well as other pertinent studies from
the plant sterol esters petition and from the studies identified by the
agency's literature search.
FDA concludes that, based on the totality of publicly available
scientific evidence, there is significant scientific agreement to
support a relationship between consumption of plant stanol esters and
the risk of CHD. The evidence that plant stanol esters affect the risk
of CHD is provided by studies that measured the effect of plant stanol
ester consumption on the two major risk factors for CHD, serum total
and LDL cholesterol.
In most intervention trials in subjects with mildly to moderately
elevated cholesterol levels (total cholesterol 300 mg/dL), plant stanol
esters were found to reduce blood total and/or LDL cholesterol levels
to a significant degree (Refs. 58, 63 and 64 (1 study), 67, 74, 77, 78,
80, 81 and 82 (1 study), 88 through 90, and 94). Moreover, HDL
cholesterol levels were unchanged in most intervention studies (Refs.
58, 67, 74, 77, 80, 88 through 90, and 94). Results in
normocholesterolemic subjects (Refs. 91 and 92) were similar to the
results in mildly to moderately hypercholesterolemic subjects.
Most of the studies in subjects with mildly to moderately elevated
cholesterol levels used ``usual'' diets in either a controlled feeding
(Refs. 58 and 74) or free-living (Refs. 63 and 64 (1 study), 67, 78, 81
and 82 (1 study), 88 through 90, and 94) situation, but three studies
used a low saturated fat, low cholesterol diet during the study (Refs.
77, 80 and 97). Both of the studies in subjects with normal blood
cholesterol levels (Refs. 91 and 92) used ``usual'' diets in a free-
living situation. Plant stanol esters have been reported to lower blood
cholesterol levels in subjects with mildly to moderately elevated
cholesterol consuming either a ``usual'' diet or low saturated fat, low
cholesterol diet and in subjects with normal blood cholesterol levels
consuming ``usual'' diets. Therefore, the evidence suggests that the
blood cholesterol-lowering response occurs regardless of the type of
background diet subjects consume.
Plant stanol esters were tested in either a spread, margarine,
butter, mayonnaise or shortening carrier and produced fairly consistent
results regardless of the food carrier and apparent differences in
processing techniques. Given the variability of amounts and food
carriers in which plant stanol esters were provided in the diets
studied, the response of blood cholesterol levels appears to be
consistent and substantial.
Based on the totality of the publicly available scientific
evidence, the agency concludes that there is significant scientific
agreement that plant stanol esters will help reduce blood cholesterol
and that such reductions may reduce the risk of CHD. Section
101.83(c)(2)(ii)(B)(1) (discussed in section V.C of this document)
specifies the plant stanol esters that have been demonstrated to have a
relationship to the risk of CHD. In the majority of clinical studies
evaluating plant stanol esters, blood total and LDL cholesterol were
the lipid fractions shown to be the most affected by plant stanol
intervention. As discussed in section I of this document, reviews by
Federal agencies and other scientific bodies have concluded that there
is substantial epidemiologic and clinical evidence that high blood
levels of total cholesterol and LDL cholesterol represent major
contributors to CHD and that dietary factors that decrease blood total
cholesterol and LDL cholesterol will affect the risk of CHD (56 FR
60727 at 60728, and Refs. 18 through 21).
Given all of this evidence, the agency is authorizing a health
claim on the relationship between plant stanol esters and reduced risk
of CHD.
V. Description and Rationale for Components of Health Claim
A. Relationship Between Plant Sterol/Stanol Esters and CHD and the
Significance of the Relationship
New section 101.83(a) describes the relationship between diets
containing plant sterol/stanol esters and the risk of CHD. In
Sec. 101.83(a)(1), the agency recounts that CHD is the most common and
serious form of CVD, and that CHD
[[Page 54702]]
refers to diseases of the heart muscle and supporting blood vessels.
This paragraph also notes that high blood total and LDL cholesterol
levels are associated with increased risk of developing CHD and
identifies the levels of total cholesterol and LDL cholesterol that
would put an individual at high risk of developing CHD, as well as
those blood cholesterol levels that are associated with borderline high
risk. This information will assist consumers in understanding the
seriousness of CHD.
In Sec. 101.83(a)(2), the agency recounts that populations with a
low incidence of CHD tend to have low blood total and LDL cholesterol
levels. This paragraph states that these populations also tend to have
dietary patterns that are low in total fat, saturated fat, and
cholesterol, and high in plant foods that contain fiber and other
components. This information is consistent with that provided in the
regulations authorizing health claims for fiber-containing fruits,
vegetables, and grain products and CHD (Sec. 101.77), soluble fiber
from certain foods and CHD (Sec. 101.81), and soy protein and CHD
(Sec. 101.82). The agency believes that this information provides a
basis for a better understanding of the numerous factors that
contribute to the risk of CHD, including the relationship of plant
sterol/stanol esters and diets low in saturated fat and cholesterol to
the risk of CHD.
Section 101.83(a)(3) states that diets that include plant sterol/
stanol esters may reduce the risk of CHD.
Section 101.83(b) describes the significance of the diet-disease
relationship. In Sec. 101.83(b)(1), the agency recounts that CHD
remains a major public health concern in the United States because the
disease accounts for more deaths than any other disease or group of
diseases. The regulation states that early management of modifiable CHD
risk factors, such as high blood total and LDL cholesterol levels, is a
major public health goal that can assist in reducing the risk of CHD.
This information is consistent with the evidence that lowering blood
total and LDL cholesterol levels reduces the risk of CHD (56 FR 60727,
58 FR 2739, and Refs. 18 through 21 and 50). Section 101.83(b)(2)
states that including plant sterol/stanol esters in the diet helps to
lower blood total and LDL cholesterol levels. FDA concludes that this
statement is scientifically valid based on the evidence that it has
reviewed on this diet-disease relationship.
B. Nature of the Claim
In new Sec. 101.83(c)(1), FDA is providing that the general
requirements for health claims in Sec. 101.14 must be met, except that
the disqualifying level for total fat per 50 g in Sec. 101.14(a)(4)
does not apply to spreads and dressings for salad, and the minimum
nutrient contribution requirement in Sec. 101.14(e)(6) does not apply
to dressings for salad. FDA has decided to except these plant sterol/
stanol ester products from the specified requirements in
Sec. 101.14(a)(4) and (e)(6) because it has determined that permitting
the health claim on such products will help consumers develop a dietary
approach that will result in significantly lower blood cholesterol
levels and an accompanying reduction in the risk of heart disease. The
basis for this decision is discussed in more detail in section V.D of
this document. The agency is requesting comments on this decision.
In Sec. 101.83(c)(2)(i), FDA is authorizing a health claim on the
relationship between diets that contain plant sterol/stanol esters and
the risk of CHD. The agency is authorizing this health claim based on
its review of the scientific evidence on this substance-disease
relationship, which shows that diets that contain plant sterol/stanol
esters help to reduce total and LDL cholesterol (Refs. 51, 57, 58, 61
and 62 (1 study), 63 and 64 (1 study), 65, 67, 74, 75, 77, 78, 80, 81
and 82 (1 study), 88 through 92, and 94). This result is significant
for the risk of heart disease because elevated levels of total and LDL
cholesterol are associated with increased risk of CHD (Refs. 18 through
21).
In Sec. 101.83(c)(2)(i)(A), FDA is requiring, consistent with other
health claims to reduce the risk of CHD, that the claim state that
plant sterol/stanol esters should be consumed as part of a diet low in
saturated fat and cholesterol. The agency acknowledges that most of the
scientific evidence for an effect of plant sterol/stanol esters on
blood cholesterol levels was provided by studies that used ``usual''
diets (Refs. 51, 57, 58, 63 and 64 (1 study), 65, 67, 74, 75, 78, 81
and 82 (1 study), 88 through 92, and 94). Some studies used low fat,
low cholesterol diets and also found