Steroli vegetali

Andrea Poli

Nutrition Foundation of Italy

& Università di Parma

Plant sterols and stanols - naturally occurring compounds structurally similar to cholesterol

HO

Cholesterol

HO

Campesterol

HO

Sitosterol HO

Sitostanol

Steroli e stanoli vegetali

Composti “naturali”

Che agiscono sulla colesterolemia LDL, prevalentemente a dosaggi “non naturali”

Attraverso un meccanismo di inibizione dell’assorbimento del colesterolo intestinale …

… che potrebbe avere valenze preventive più interessanti del previsto

Vegetable oils – rich sources of plant sterols

• Corn oil (refined) 715–950 mg/100g

• Rapeseed oil (refined) 250–731 mg/100g

• Soybean oil (refined) 221–328 mg/100g

• Olive oil (extra virgin) 144–150 mg/100g

• Palm oil (refined) 49–61 mg/100g

Plant sterol content in foods

Fruits, vegetables, cereals & nuts also contain plant sterols

Sources: Trautwein and Duchateau, Phytosterols: Sources and Metabolism in Nutrition and Cancer Prevention 2005; Normen

et al. Eur J Nutr 1999; Normen et al. J Food Comp and Analysis 2002; Weilhrauch et al. Am Diet Assoc 1978

• Apple (one small, 100g): 13 mg

• Orange (one small, 100g): 24 mg

• Broccoli (one cup chopped, 100g): 39 mg

• Carrot (one cup chopped, 100g): 16 mg

• Tomato (one medium, 100g): 4.7 mg

• Wholemeal bread (3 slices, 100g): 86 mg

Data from the Netherlands Cohort Study*

Total plant sterol intake: 280 mg/day 240 mg/day

Total plant stanol intake: 28 mg/day 23 mg/day

Data from the EPIC Norfolk population**

Total plant sterol intake: 310 ± 108 mg/day 303 ± 100

mg/day

Cholesterol intake: 260 mg ± 105 mg/day

Data from the national FINDIET survey***

Total plant sterol intake: 305 mg/day 237 mg/day

Cholesterol intake: 284 mg/day 201 mg/day

*Normen et al., Am J Clin Nutr, 2001

** Andersson et al., Eur J Clin Nutr, 2004

*** Valsta et al., Br J Nutr, 2004

Plant sterol/stanol intakes in various populations

Reduction of cholesterol absorption by plant sterols/stanols: overview of studies

adopted from Normen et al.: "Role of plant sterols in cholesterol lowering” in: Phytosterols as Functional Food Components and Nutraceuticals, 2004

free sterols

stanol esters

log. sterol and stanol esters

log. free sterols/stanols

free stanols

sterol esters

-70

-60

-50

-40

-30

-20

-10

0 0 2 4 6 8 10 plant sterols g/d

%

Reduction of cholesterol absorption by plant sterols/stanols: overview of studies

adopted from Normen et al.: "Role of plant sterols in cholesterol lowering” in: Phytosterols as Functional Food Components and Nutraceuticals, 2004

free sterols

stanol esters

log. sterol and stanol esters

log. free sterols/stanols

free stanols

sterol esters

-70

-60

-50

-40

-30

-20

-10

0 0 2 4 6 8 10 plant sterols g/d

%

2 L di olio di mais

10 Kg di mele o arance

Plant sterol/stanols intake leads to reduction in

intestinal cholesterol absorption*

-40

-30

-20

-10

0

-36%

-26%

Sterols Stanols C

ho

leste

rol

ab

so

rpti

on

% r

ed

ucti

on

fro

m c

on

tro

l

Jones et al J Lipid Res, 2000

* as measured with the

dual stable isotope ratio

method with 13C- (oral) and

D7 -Cholesterol (iv)

Intake of 23 g/d of spread providing 1.8 g/d of plant sterols or stanols for 3 weeks resulted

in a 13.2 % reduction in LDL-cholesterol

Fitosteroli: meccanismo d’azione

Gylling E et al, Atherosclerosis 2014

Intestinal absorption of plant sterols is low compared to cholesterol

adapted from Bosner et al. J Lipid Res, 1999

& Ostlund et al. Am J Physiol Endocrinol Metab, 2002

0

Cholesterol

Campesterol

Sitosterol

Campestanol

Sitostanol

10

20

30

40

50

60

% absorption

56

1.9 0.5 0.2 0.04

Plasma concentrations of plant sterols are ~200 times lower than of cholesterol

* based on data from the MRFIT-study

** based on overview of published data on basal plant sterol concentrations

Plasma plant sterols**#

mm

ol/L

0

0.01

0.02

0.03

0.04

0.05

0.06

0

2

4

6

8

10

12

mm

ol/L

Plasma total cholesterol*

#20-100 times lower compared to

plasma concentrations in subjects with

homozygous sitosterolemia

data of ~ 30 placebo-controlled initiated studies with phytosterol-enriched spreads

-16

-12

-8

-4

0 0.5 1 1.5 2 2.5 3 3.5

Plant sterol intake (g/day)

%

red

ucti

on

of

LD

L-c

ho

leste

rol

data (mean plus 95% confidence interval) from meta-analysis of 41 studies

with phytosterols or stanols

-6

-10

Cholesterol lowering with plant sterols in fat-based foods: dose-response relationship

0.0

Katan M et al, Mayo Clin Proc. 2003

-2

-14

Cholesterol lowering with plant sterols and stanols: a meta-analysis

Ras RT et al. Brit J Nutr 2014

Mendelian Randomization studies on the risk of Coronary

Heart Disease (CHD)

Henning J, et al. Eur Heart J 2014

Racette BS, AJCN, 2010

Dose effects of dietary phytosterols on cholesterol metabolism: a controlled study

Racette BS, AJCN, 2010

Dose effects of dietary phytosterols on cholesterol metabolism: a controlled study

Racette BS, AJCN, 2010

Dose effects of dietary phytosterols on cholesterol metabolism: a controlled study

-10% -5%

Impact of intake occasion on cholesterol lowering of single-

dose plant sterol intake

*statistically significant #100 g serving size taken once a day delivering 2.8 g plant sterols

Doornbos et al., Eur J Clin Nutr, 2006

Intake with vs. without a meal enhances the cholesterol lowering effect

without meal with meal

-4.4

-6.8

-6.0

-9.4 -8

-6

-4

-2

0 TC LDL-Cholesterol

% r

ed

ucti

on

*

*

Colesterolo

dietetico

300 mg/die

Colesterolo

1000 mg/die

DARM

Escrezione Fecale

Colesterolo: un complesso sistema omeostatico a tre vie

Sintesi epatica di

Colesterolo Bile

Intestino

Assorbimento

intestinale

Captazione

recettoriale delle

LDL plasmatiche

Assorbire o sintetizzare?

J Lipid Research 2009; 50: 1927-35.

Caratteristiche dei pazienti CHD e dei controlli sani nella coorte del Framingham offspring Study:

a- profilo lipidico

J Lipid Research 2009; 50: 1927-35.

Caratteristiche dei pazienti CHD e dei controlli sani nella coorte del Framingham offspring Study:

b- markers di assorbimento e sintesi del colesterolo

J Lipid Research 2009; 50: 1927-35.

casi controlli p

Odd Ratios di essere un paziente CHD nella coorte del Framingham offspring Study: ruolo dei markers di

assorbimento e sintesi del colesterolo e dei loro rapporti

J Lipid Research 2009; 50: 1927-35.

Silbernagel G et al, J Am Coll Cardiol, 2013

Cholesterol Absorption Markers and CVD: a metanalysis

Silbernagel G et al, J Am Coll Cardiol, 2013

Cholesterol Absorption Markers and CVD: a metanalysis

PROCAM study!

The Myocardial Infarction Genetics Consortium Investigators, N Engl J Med 2014

Inactivating mutation in NPC1L1 and protection from CHD

The Myocardial Infarction Genetics Consortium Investigators, N Engl J Med 2014

Inactivating mutation in NPC1L1 and protection from CHD

The Myocardial Infarction Genetics Consortium Investigators, N Engl J Med 2014

Inactivating mutation in NPC1L1 and protection from CHD

BLOOD

Chylomicrons

Remnants

DIET

Micelles

Free cholesterol

Chole

ste

rol

Bile acids

Unstirred

water

layer

Synthesis

FC biosynthesis

ACAT

Cholesteryl

Ester (CE) FC

ENTEROCYTE

Bru

sh

Bord

er

Plaque

formation

CE

CE Bile acid

sequestrants

X

Sterols/

stanols

X X

Statins

X

Cholesterol Absorption Inhibitors (e.g., ezetimibe)

X

Cholesterol Absorption: an “unsafe” metabolic avenue?

Oxysterols

Sato K et al, J Atheroscl Thromb 2012

Sato K et al, J Atheroscl Thromb 2012

Sato K et al, J Atheroscl Thromb 2012

p < 0,05

p = n.s.

Kinlay S et al, J Am Coll Cardiol 2007

LDL-c and CRP reduction in clinical trials: a meta-analysis.

-37%

-50%

JUPITER

-10%

-3/6%

Phytosterols

Plant sterol enriched diet (2 g/day) reduces sdLDL in hypercholesterolemic children (4-16 y old) in 6/12 months

Garoufi A et al, Ital J Pediatr, 2014

Colesterolo dietetico e rischio di diabete: una recentissima metanalisi

Tamez M et al, Brit J Nutr 2016

Colesterolo

dietetico

300 mg/die

Colesterolo

1000 mg/die

DARM

Escrezione Fecale

Colesterolo: un complesso sistema omeostatico a tre vie

Sintesi epatica di

Colesterolo Bile

Intestino

Assorbimento

intestinale

Captazione

recettoriale delle

LDL plasmatiche

High basal fractional cholesterol synthesis is associated with nonresponse of plasma LDL

cholesterol to plant sterol therapy

Rideout TC et al, Am J Clin Nutr 2010

-16

-12

-8

-4

0 0.5 1 1.5 2 2.5 3 3.5

Plant sterol intake (g/day)

% re

duction o

f LD

L-c

hole

ste

rol

-6

-10

Cholesterol lowering with plant sterols in fat-based foods: dose-response relationship

0.0

Risposta bilanciata

Tendenzialmente Assorbitori

Tendenzialmente Sintetizzatori (*)

(*) oppure con bassa aderenza alla terapia

Low Fat Yogurt Enriched in Plant Stanols Effectively

Lowers LDL-C

Run-in

period Experimental

period

Wash-out

period 108

104

100

96

92

88

0 2 4 6 8

% o

f w

eek

3 v

alu

es

Weeks

Control group Experimental group Mensink RP et al, Atherosclerosis, 2002

-40

-30

-20

-10

0 healthy diet*

Cholesterol-lowering effect of plant sterols additive to

healthy diet & lipid-lowering medication

healthy diet*

Statin

treatment

plant sterol

enriched

foods*

healthy diet*

plant sterol

enriched

foods**

Katan et al Mayo Clin Proc, 2003; Edwards & Moore BMC Family Practice, 2003

LD

L-c

ho

leste

rol re

du

ctio

n, %

*low in saturated fat and cholesterol

**2-3 g/d of plant sterols in the form of enriched foods

-40

-30

-20

-10

0 healthy diet*

Cholesterol-lowering effect of plant sterols additive to

healthy diet & lipid-lowering medication

healthy diet*

Statin

treatment

plant sterol

enriched

foods*

healthy diet*

plant sterol

enriched

foods**

Katan et al Mayo Clin Proc, 2003; Edwards & Moore BMC Family Practice, 2003

LD

L-c

ho

leste

rol re

du

ctio

n, %

*low in saturated fat and cholesterol

**2-3 g/d of plant sterols in the form of enriched foods

L’effetto osservato (-9/10%) equivale

a raddoppiare/quadruplicare la dose

della statina impiegata (regola del 6%)

Rischio Cardiovascolare, distanza dal target e approccio terapeutico appropriato secondo la nota 13 del luglio 2014:

i dati dello studio CHECK

Poli A et al., G Ital Arter 2015

C – Distanza dal target (soggetti non a target, n=2271)

3,8 milioni

Area del life style “potenziato”

6,5 milioni 2,8 milioni

Area del generico Area dell’efficacia massimale

Summary and conclusions:

Gylling E et al, Atherosclerosis 2014

Summary and conclusions - 2:

Gylling E et al, Atherosclerosis 2014