Plant stanol esters in human studies Professor Helena Gylling University of Kuopio

2 Human studies A search for human studies with the word ”stanol ester” from PUBMED (A service of the U.S.National Library of Medicine and the National Institutes of Health): 67 studies reviews: 15 clinical studies: 32 adults,19+ years of age: 24 children 0-18 years of age: 9

3 Human studies, cont Men young adult middle-aged and elderly Women premenopausal postmenopausal Children Mild hypercholesterolemia Familial hypercholesterolemia CHD patients Patients with type 2 diabetes Patients on cholesterol-lowering drugs: bile acid sequestrants statins

4 Miettinen et al, NEJM 1995:333:

CHOLESTEROL 1. NO STANOL FOR TWENTY DAYS 2. STANOL-LOVASTATIN FOR TREE WEEKS 3. NO STANOL FOR SEVEN DAYS TREATMENT YEARS PLANT STANOL (3g/d) ESTER MARGARINE mmol / l CAMPESTEROLSITOSTEROLSITOSTANOL Miettinen and Gylling 2006 PLANT STANOL (3g/d) ESTER MARGARINE

6 Stanol ester in type 2 diabetes and in combination with statins Gylling and Miettinen 1996

7 Stanol ester + statins Thompson 2005

8 50 randomised studies with plant stanol/sterol esters mainly in spread: A meta- analysis Age, yearsNumber of studies LDL-C reduction (95% CI) % LDL-C reduction ( )8.0% (0-0.5)10.0% ( )10.5% ( )10.3% ( )9.6% Katan et al 2003

9 The efficacy of plant stanol esters % LDL-C reduction and dose of stanol/sterol. A meta-analysis of 42 studies Katan et al 2003 % LDL-C reduction Dose of stanol/sterol, g/day

10 Stanol ester in low-fat products Salo and Wester 2005 n=40, placebo- controlled study

11 Stanol ester in fat-free milieu: An experiment in candy type pastilles Consumption of stanol ester-containing pastilles for 7 days by colectomized patients (n=9) Serum lipidsBaselineChange Total cholesterol, mmol/l4.77± ±0.12* Esterified, mmol/l3.58± ±0.10* Free, mmol/l1.19± ±0.02* Esterification %74.90± ±0.25 LDL cholesterol, mmol/l2.91± ±0.12* HDL cholesterol, mmol/l1.46± ±0.03 Triglycerides, mmol/l0.89± ± % -14% Nissinen et al 2006

12 Metabolic effects of plant stanols. Results form 4 studies, 57 subjects VariablesBaselineChange Serum cholesterol, mmol/l 5.5±1-0.5±0.1* Fecal fat, g/kg/d 1± ±0.0 Cholesterol absorption, %37±2-17±2* Serum campesterol/cholesterol305±18-103±9* Cholesterol synthesis, mg/kg/d 16±1+3±1* Serum lathosterol/cholesterol187±9+24±4* Cholesterol turnover, mg/kg/d 17±1+3±0.4* Bile acid synthesis, mg/kg/d 9±1+1±0.5 Miettinen and Gylling 2003

13 Two aspects, which have to be dealt in future studies Serum plant sterols The concept of responsiveness in North-Karelia one-year study, 12% of subjects were low- responders. Compliance was so carefully checked as is possible in free-living populations. What is the reason for responsiveness?

14 y = x r = y = x r = Serum lathosterol, 10 2 * μg / mg of cholesterol Serum campesterol, 10 2 * μg / mg of cholesterol Vascular campesterol, 10 2 * μg / mg of cholesterol Miettinen et al 2005 Sterols in atheroma and in serum

15 Sterol accumulation in red blood cells during stanol- and sterol ester margarine consumption in children Ketomäki et al 2003

16 Ketomäki et al 2004 Serum sitosterol to cholesterol ratio in a homozygous FH patient and in 2 heterozygotes during stanol-and sterol ester consumption

17 Serum cholesterol and plant sterols during 1- year stanol ester consumption Gylling et al 1999

18 To conclude: We know that stanol ester decreases serum plant sterols which is favorable. Sterol ester increases them, but we need more information, whether this is harmful.

19 The profile of cholesterol metabolism: -- high absorption - low synthesis -- low absorption - high synthesis Gylling et al 2004

20 Responsiveness to absorption inhibition with stanol ester SterolAbsorptionBaselineStatinStatin+ Stanol ester Cholesterol mmol/l Low (n=15) 6.11± ± ±0.17 High (n=15) 5.87± ± ±0.12* * significantly different from low Gylling and Miettinen 2002

21 Responsiveness to absorption inhibition with stanol ester, cont. SterolAbsorptionStatinStatin+stanol ester CholesterolLow-1.30±0.27*-0.26±0.16 High-1.34±0.14*-0.37±0.11* Lathosterol ratioLow-99.0±21.2*+26.9±8.6* High-29.2±13.6*ª+15.2±4.8* Campesterol ratioLow+80.5±8.4*-66.7±10.9* High+99.9±17.6*-111.0±18.7*ª ª significantly different from low; * significantly different from previous period Gylling and Miettinen 2002

22 Responsiveness in children with FH Hedman et al 2006

23 Responsiveness in children with FH, cont. Hedman et al 2006

24 To conclude: Especially subjects with high absorption are responding well to stanol ester. These subjects may not need statins at all, and if so the dose can be smaller.

25 Conclusions Stanol ester as part of healthy diet effectively and safely lowers serum total and LDL cholesterol in different populations Cholesterol reduction is from 10% to 14% Well-documented worldwide No side effects Included in cholesterol-lowering lifestyle recommendations (e.g. American Heart Association, ATPIII, national recommendations) Stanol ester especially effective for subjects with high cholesterol absorption?