Nutraceuticals in

Lipid-Lowering Treatment

Prof. Manfredi Rizzo, MD, PhD

The term nutraceutical is a chimerical word,

resulting from the fusion of “nutrition” and

“pharmaceutical”.

it was first formulated by Stephen Defelice

in 1989:

“Nutraceuticals are food or part of a food

that provides medical or health benefits,

including the prevention and/or treatment of

a disease”

Nutraceuticals: Definition

A “dietary supplement” is a product intended to supplement one or more nutrients,

with the intent of increasing their total daily intake.

A “functional food” is instead defined as a food product to be taken as a part of the

usual diet in order to have beneficial effects that go beyond basic nutritional

function.

Functional foods can be enriched with ingredients that usually are not present in

that particular food, or contain an amount of a specific nutrient larger than usual.

Food and Drugs Administration

(FDA): Definitions

The European Commission regulates the nutraceutical market through the

European Food Safety Authority (EFSA), which authorizes the labeling of food

products with health claims.

A health claim must be based on accepted scientific evidences, which

demonstrate a significant effect in humans and a cause-and-effect relationship

between the consumption of the food and claimed effect on humans.

European Food Safety

Authority (EFSA):

Regulations

The literature counts over 40 nutraceuticals with a supposed beneficial effect on

lipid metabolism.

Yet, only few of them have proven efficacy in reducing serum lipids and ultimately

cardiovascular risk.

Many trials investigating the effect of nutraceuticals on lipid metabolism have

important methodological drawbacks in terms of study design, population

characterization and outcome selection.

Nutraceuticals as Lipid-Lowering Treatment

EVIDENCES FOR:

1. Phytosterols

2. Policosanol

3. Flavonoids

4. Soy Protein

5. Red yeast rice

6. Resveratrol

Plant sterols (including beta-sitasterol, campesterol and stigmasterol) have similar structure and

cellular function to cholesterol, and are present in vegetable oils, nuts, and seeds. Plant stanols

(beta-sitastanol and campestanol) are saturated derivatives of sterols

Phytosterols compete with cholesterol for intestinal absorption, thus modulating TC levels.

Phytosterols have been added to spreads and vegetable oils (functional margarine, butter, and

cooking oils) as well as yoghurt and other foods.

1. Phytosterols

The dietary intake of plant sterols ranges between

an average of 250 mg/day in Northern Europe to

500 mg/day in Mediterranean countries.

Phytosterols and plasma lipids:

systematic review and meta-analysis

LITERATURE SEARCH

Effect of Phytosterols on TC and LDL-C

Effect of Phytosterols on HDL-C and TG

Phytosterols and plasma lipids: systematic review and meta-analysis

MAIN RESULTS

Overall Effect of Phytosterols on LDL-C:

-8.5% relative change vs. placebo

Atherosclerosis

230 (2013) 336e346

Effect of Plant Sterols vs. Plant Stenols on LDL-C

Atherosclerosis

230 (2013) 336e346

EFSA: A daily intake of 3g in matrices approved (yellow fat spreads, dairy products,

mayonnaise and salad dressings) lowers LDL-C by 11.3%.

The minimum duration required is 2 to 3 weeks.

EFSA and FDA on Phytosterols

FDA: Plant sterol/stanol esters may reduce the risk of CHD.

Plant sterol/stanol esters in the diet help to lower blood TC and LDL-C.

Daily dietary intake levels associated with reduced risk of CHD are:

≥1.3 g/day of plant sterol esters.

≥3.4 g/day of plant stanol esters.

Policosanol is an antilipemic agent that includes mixtures of

aliphatic primary alcohols extracted from sugarcane wax.

Its main components are octacosanol (62.9%), triacontanol

(12.6%), and hexacosanol (6.2%).

Policosanol is used for reduction of LDL levels in more than

25 countries, mainly in the Caribbean and South America.

2. Policosanol

Dose and treatment duration response with Policosanol

Percent change comparison between Policosanol and Phytosterols

EFSA: Inconsistent effects on TC and LDL-C.

There is no evidence of a mechanism by which policosanols from sugar cane

wax could exert the claimed effect.

A cause and effect relationship has not been established between the

consumption of policosanols from sugar cane wax and maintenance of

normal blood LDL-C concentrations.

EFSA and FDA on Policosanol

FDA: This product is not intended to diagnose, treat, cure, or prevent any disease.

Flavonoids (or bioflavonoids) (from the Latin word flavus, meaning yellow - their color in nature)

are a class of plant secondary metabolites.

Flavonoids were referred to as Vitamin P (probably because of the effect they had on the

permeability of vascular capillaries) from the mid-1930s to early 50s, but the term has since

fallen out of use.

Foods with a high flavonoid content include parsley, onions, blueberries and other berries, black

tea, green tea, bananas, all citrus fruits, Ginkgo biloba, red wine, and dark chocolate

3. Flavonoids

Flavonoid composition of commonly consumed flavonoid-rich food

Flavonoids and plasma lipids:

systematic review and meta-analysis

LITERATURE SEARCH

Effect of Flavonoids on LDL-C

Effect of Flavonoids on HDL-C

Soy protein has been used since 1959 in foods for its

functional properties. Its popularity has increased due

to the use in health food products.

Soy protein is used in a variety of foods, such as

salad dressings, soups, meat analogues, beverage

powders, cheeses, frozen desserts, whipped topping,

infant formulas, breads, breakfast cereals, pastas,

and pet foods.

Soy protein has a modest LDL-C-lowering effect (3–

5%) and most likely in subjects with hyper-TC.

4. Soy Protein

Effect of Soy Protein on TC and LDL-C

EFSA: A cause and effect relationship has not been established between the

consumption of isolated soy protein and a reduction in blood LDL-C.

EFSA and FDA on Soy

FDA: The addition of soy protein to a diet that is low in saturated fat and

cholesterol may help to reduce the risk of CHD.

The food product shall contain at least 6.25 g of soy protein per

reference amount customarily consumed of the food product.

Red yeast rice (RYR) is a fermented product of rice used

for centuries in China to make rice wine, as a flavor

enhancer, as a food colorant and to “promote digestion

and circulation”.

In RYR there is a substance named monacolin K, which

inhibits cholesterol synthesis with a statin-like mechanism

of action.

Yet, the lipid-lowering effect of RYR effect might be only

partially attributable to monacolin K content. Indeed, RYR

contains about 10 different monacolins as well as

phytosterols (beta-sitosterol and campesterol).

5. Red Yeast Rice

Red Yeast Rice and plasma lipids:

systematic review and meta-analysis

LITERATURE SEARCH

Effect of Red Yeast Rice on TC

Effect of Red Yeast Rice on TG

Effect of Red Yeast Rice on LDL-C

Effect of Red Yeast Rice on HDL-C

EFSA: A cause and effect relationship has been established between the consumption

of monacolin K from red yeast rice and maintenance of normal blood LDL-C.

Daily dietary intake levels associated with the claimed effect:

10 mg of monacolin K from fermented red yeast rice preparations.

EFSA and FDA on Red Yeast Rice

FDA: The red yeast rice powder contains greater than 0.4% lovastatin (monacolin K).

The U.S. District Court for the District of Utah affirmed that red yeast rice

products that contain significant amounts of lovastatin are subject to

regulation as drugs and are not dietary supplements.

Resveratrol is a natural polyphenol with several health

benefits that is generally contained in grapes and its

derivates, peanuts and berries.

Levels of resveratrol differ considerably between plant

species. In blueberries, resveratrol content is

approximately 32 ng/g, which is lower compared with

levels of up to 2,000 and 3,5000 ng/g in peanuts and

grapes, respectively.

Many credit the ‘French Paradox’, in which moderate wine

consumption was associated with decreased risk of CHD,

as the consequence of red wine’s reasonably high

resveratrol level (up to 14 mg/l).

6. Resveratrol

Resveratrol and plasma lipids:

systematic review and meta-analysis

LITERATURE SEARCH

Effect of Resveratrol on LDL-C

Effect of Resveratrol on HDL-C

SUMMARY – ALL DATA

2. Yet, as stated by the ESC/EAS Guidelines:

“Overall, the available evidence on functional foods so far

identified in this field is lacking; the major gap is the

absence of diet-based intervention trials of sufficient

duration to be relevant for the natural history of

dyslipidaemia and CVD.”

CONCLUSIONS

1. Several nutraceuticals have significant effects on plasma lipids, although

not all of them are approved by FDA and EFSA for treating lipid disorders.