The Science of Plant Stanol Ester

Contents Background Plant stanol ester and LDL-cholesterol lowering Dose-response of plant stanol ester with high daily intake Plant stanol ester is widely recommended for cholesterol lowering as a part of a healthy diet 1

Why lower LDL cholesterol? Lowering LDL cholesterol is the primary target in dyslipidemia management and cardiovascular disease prevention. Diet and other lifestyle changes always form the basis for the treatment. 2 British Heart Foundation Coronary Heart Disease Statistics. British Heart Foundation Statistics Database 2000.

Plant stanol ester reduces LDL cholesterol Plant stanol ester Reduces total and LDL cholesterol on average by 10% Does not affect HDL cholesterol 3 2 G OF PLANT STANOLS PER DAY REDUCES LDL-CHOLESTEROL BY 10%

Recognized effect Plant stanol ester has been granted strong health claims by the EU commission US FDA Several official guidelines aiming at reducing the risk of CHD recommend consumption of functional foods with plant stanols as part of the diet 4

Proven efficacy The cholesterol lowering efficacy of Plant stanol ester has been proven in over 60 clinical studies: Healthy women, men and children Normocholesterolemic subjects Subjects with modestly elevated and high cholesterol levels Type 1 and 2 diabetics Subjects with metabolic syndrome CAD patients As a part of normal western diet As a part of strict cholesterol lowering diet With statin medication In different populations all over the world 5

Molecular structures: Cholesterol, plant stanols and sterols 6

Mechanism of action 7 WITH PLANT STANOL ~20% of cholesterol is absorbed WITHOUT PLANT STANOL ~50% of cholesterol is absorbed CholesterolPlant stanol ester Plant stanol ester reduces cholesterol absorption in small intestine.

Adapted from Gylling et al. Circulation 1997; 96: Reduced cholesterol absorption Plant stanol ester reduces the absorption of both dietary and biliary cholesterol. 8 Biliary cholesterol absorbed Dietary cholesterol absorbed Normal diet Normal diet + plant stanol ester Absorption (mg/d) PLANT STANOL ESTER REDUCES ABSORPTION OF DIETARY AND BILIARY CHOLESTEROL

Plant stanol ester and LDL-cholesterol lowering

10 Athyros et al. Nutr Metab Cardiovasc Dis 2011; 21(3): Control spread Mediterranean diet Plant stanol ester spread (2 g plant stanol/d) CHANGE IN LDL CHOLESTEROL * * LDL reduction (%) Months * ** *p <0.01 vs. control Fast lowering of LDL cholesterol Fast and efficient LDL cholesterol reduction with plant stanol ester.

Miettinen et al. New Engl J Med 1995; 333: The LDL cholesterol lowering effect of plant stanol ester is sustained with daily use. Sustainable efficacy with daily use Plant stanol ester spread (1.8 g plant stanol/d) Control spread Plant stanol ester spread (2.6 g plant stanol/d) CHANGE IN SERUM TOTAL CHOLESTEROL LEVELS * * Cholesterol (mg/dl) Months Intervention *p<0.05 vs. control * * * *

Plat et al. Eur J Clin Nutr 2000; 54: PLANT STANOL ESTER IS AS EFFECTIVE IF DIVIDED OVER SEVERAL MEALS OR TAKEN ONCE A DAY Control period Plant stanol ester spread 1 x Day Plant stanol ester spread 3 x Day *p<0.001 vs. control LDL-cholesterol (mmol/l) * Once a day is enough 12 * The efficacy of plant stanol ester is independent of consumption frequency.

Blair et al. Am J Cardiol 2000; 86: Control spread * * * INCREMENTAL LDL-CHOLESTEROL LOWERING OF PLANT STANOL ESTER IN STATIN USERS Plant stanol ester spread (3 g plant stanol/d) Change in LDL cholesterol (%) Weeks 10 % plant stanol ester specific effect Additive to statins Plant stanol ester adds to the cholesterol-lowering effect of statins. 13 *p<0.001 vs. control

Hallikainen and Uusitupa. Am J Clin Nutr 1999; 69: Additive to a healthy diet Plant stanol ester adds to the cholesterol- lowering effect of a healthy diet. 14 Cholesterol-lowering diet Cholesterol-lowering diet + plant stanol ester (2.3 g plant stanol/d) Change % in LDL cholesterol EFFECTIVE AS PART OF A STRICT CHOLESTEROL-LOWERING DIET *Plant stanol ester specific effect a= p<0.01 vs. baseline b= p<0.001 vs. baseline and p<0.01 vs. control LDL cholesterol a b

Athyros et al. Nutr Metab Cardiovasc Dis 2011; 21(3): EFFECTIVE REDUCTION IN THE ESTIMATED RISK OF CORONARY ARTERY DISEASE (CAD) Control spread Change (%) in 10-year estimated CAD risk (Framingham risk engine) Mediterranean diet Plant stanol ester spread (2 g plant stanols/d) Months *p<0.05 vs. control As effective as Mediterranean diet Plant stanol ester is as effective on lowering the estimated coronary artery disease risk as adopting Mediterranean diet. 15 * * * * * * *

Dose-response of plant stanol ester with high daily intake

Gylling et al. Clin Nutr 2010; 29: Change (%) Control (n=24) Plant Stanol Ester (8.8 g/d plant stanols) CHANGE IN LDL CHOLESTEROL DURING THE 10-WEEK STUDY LDL Cholesterol * *p<0.01 vs. control Better efficacy with a higher dose Additional cholesterol reduction with 8.8 g plant stanols a day. 17

Mensink et al. Am J Clin Nutr 2010; 92: Dose-dependent reduction LDL cholesterol reduction is dose-dependent with high intake of plant stanol ester. 18 Change in LDL cholesterol (mmol/l) compared to the baseline Plant stanol intake (g/day) *p<0.01 vs. control * * * DOSE-DEPENDENT REDUCTION IN LDL CHOLESTEROL WITH PLANT STANOL ESTER

Musa-Veloso et al. Prostaglandins Leukot Essent Fatty Acids 2011; 85: Better maximal efficacy Significantly better maximal efficacy with plant stanol ester. 19 LDL cholesterol reduction (%) Plant sterol ester Plant stanol ester Plant stanols/sterols (g/day)

Plant stanol ester is widely recommended for cholesterol lowering as a part of a healthy diet

International Atherosclerosis Society, 2013 American Diabetes Association, 2013 European Atherosclerosis Society, 2013 European Society of Cardiology, 2012 National Heart, Lung, and Blood Institute & National Institutes of Health & American Academy of Pediatrics, 2011 European Society of Cardiology & European Atherosclerosis Society, 2011 The Australian Heart Foundation, 2009 American Academy of Pediatrics, 2008 American Diabetes Association & American College of Cardiology, 2008 American Heart Association & American College of Cardiology, 2006 Joint British Societies, 2005 International Atherosclerosis Society, 2005 Joint WHO/FAO Expert Consultation, 2003 International Lipid Information Bureau, 2003 National Cholesterol Education Program & National Institute of Health, 2002 Expert bodies recommend the use of plant stanols 21

ESC/EAS Guidelines for the management of dyslipidemias The magnitude of the effect of functional foods enriched with phytosterols is graded ’+++’ (=highest possible) and the level of evidence is of class ’A’ ’Based on the available evidence, foods enriched with phytosterols (1-2 g/day) may be considered for individuals with elevated TC and LDL-C values in whom the total CV risk assessment does not justify the use of cholesterol-lowering drugs.’ ’Functional food containing phytosterols additionally reduce LDL-C levels by up to 5-10% in patients taking stable dose of a statin, and this combination is also well tolerated and safe.’ ESC/EAS,

European Guidelines on cardiovascular disease prevention in clinical practice ‘Functional foods containing phytosterols (plant sterols and stanols) are effective in lowering LDL cholesterol levels by on average 10%, when consumed in amounts of 2 g/day. The cholesterol-lowering effect is additional to that obtained with a low-fat diet or use of statins. Some recent research indicates that, especially for stanols, further cholesterol reduction can be obtained with higher doses.’ ESC,

An International Atherosclerosis Society Position Paper: Global Recommendations for the Management of Dyslipidemia ‘Consider using plant sterols/stanols (2 g/day) as a dietary adjunct [--] to further lower LDL-C levels. Several nations place limits on amounts of plant sterols/stanols that are allowed as nutritional supplements (because of questions about potential benefits vs. possible side effects). However, if plant sterols/stanols are available, they are a useful adjunct to lowering of LDL-C by dietary means.‘ IAS,

Important step before medication Usage of plant stanol ester is recommended before starting medication. 25 Plant stanol ester If LDL goal not reached in 6 weeks, add Pharmaceuticals Monitor adherence to TLC diet after 4-6 months Therapeutic Lifestyle Changes If LDL goal not reached with TLC in 6 weeks, add NCEP ATPIII, 2002.

Proven efficacy when combined with statins For patients already on statins, combining plant stanol ester provides additional 10% effect in LDL reduction. 26 Therapeutic Lifestyle Changes Pharmaceuticals Plant stanol ester Blair et al. Am J Cardiol 2000; 86: De Jong et al. Br J Nutr 2008; 100:

The most effective dietary way to lower cholesterol 27 LDL cholesterol reduction (%)