3. HEARTS & MINDS Lowering Cholesterol with Plant Stanol Ester Opening Remarks Herbert Schuster, M.D., Ph.D. Humboldt University Berlin, Berlin, Germany Chairman

4. AGENDA Organizational Issues Introduction Programme Overview

5. International Cardiovascular Disease Statistics 2005; AHA. Global Burden of Cardiovascular Disease In 2002: CVD contributed to approximately a third of all global deaths (17 million) 80% of burden is in low- and middle-income countries By 2020: CHD and stroke will become the leading cause of death and disability worldwide Mortality from CVD will increase to 20 million CVD lowers quality of life but clinical care is also costly

6. Environmental Risk Factors Illustrated by Peter Breugel

7. Lifestyle Changes are the Basic Principle of Cardiovascular Risk Prevention Oslo Diet Heart Study 412 men with CHD, 5 year controlled trial Treatment group randomized to low saturated fat, low cholesterol, high polyunsaturated fat diet Serum cholesterol reduced by 14% 33% reduction in myocardial infarction, 26% decrease in coronary heart disease mortality Leren et al. Acta Med Scand 1966; 466:1

8. Lifestyle Changes are the Basic Principle of Cardiovascular Risk Prevention Lifestyle Heart Trial 41 male and female CHD patients Randomized to <10% fat diet, exercise and meditation (Rx group) versus Step 1 diet At one year 37% LDL-Cholesterol reduction, 22% weight loss, and 1.8% regression in Rx group versus 2.3 progression in control group (quantitative coronary angiography) At 5 years 20% LDL-Cholesterol reduction, 3.1% regression in Rx groups versus 11.8% progression in control group (n=35) Ornish et al. Lancet 1990; 336:129-133, and JAMA 1998; 280:2001-2007

9. Major coronary events Major vascular events Prospective meta-analysis of data from 90.056 participants in 14 randomized statin trials CTT Collaborators. Lancet. 2005;366:1267–78. Proportional reduction in event rate (%  SE) Reduction in LDL-C in mmol/l (mg/dl) 50 40 30 20 10 0 -10 0.5 (19) 1.0 (38) 1.5 (58) 2.0 (77) 0.5 (19) 1.0 (38) 1.5 (58) 2.0 (77) 50 40 30 20 10 0 -10 Statin Trials Reinforce the Need to Consider Substantial LDL-Cholesterol Reduction

10. Grundy SM et al. Circulation. 2004;110:227-39. * Therapeutic option 190 160 130 100 70 70 mg/dl= 1.8 mmol/l; 100 mg/dl= 2.6 mmol/l; 130 mg/dl= 3.4 mmol/l; 160 mg/dl= 4.1 mmol/l LDL-C level [mg/dl] CHD or CHD risk equivalents High Risk ≥2 risk factors Moderately High Risk ≥ 2 risk factors Moderate Risk <2 risk factors Lower Risk (10-yr risk >20%)(10-yr risk 10-20%)(10-yr risk <10%) Goal 100 mg/dl or optional 70 mg/dl* or optional 100 mg/dl* Goal 130 mg/dl Goal 160 mg/dl Existing LDL-C goals Proposed LDL-C goals Goal 130 mg/dl NCEP ATP III: LDL-C Goals Including 2004 Proposed Modifications

11. Key Questions in Cardiovascular Disease Prevention HOW LOW SHOULD WE GO? HOW EARLY SHOULD WE START?

12. 30 20 10 0 50th Percentile Sequence variants in the PCSK9 gene increase levels of LDL receptors in the liver Frequency (%) 30 20 10 0 050100150200250300 Cohen C et al. N Engl J Med. 2006;354:1264-72. No PCSK9 46L Allele (N=9223) PCSK9 46L Allele (N=301) Plasma LDL-Cholesterol in white subjects (mg/dl) (mean age 54 years) Subjects with a PCSK9 Gene Variant have a 15% Lifelong Reduction in LDL-Cholesterol

13. Cohen C et al. N Engl J Med. 2006;354:1264-72. 12 8 4 0 Coronary Heart Disease (%) NoYes Subjects with the mean age of 54 years with the PCSK9 sequence variation have a significant 47% CHD risk reduction (hazard ratio 0.50; 95% confidence interval 0.32 to 0.79; p=0.003) p=0.003 PCSK9 46L Lifelong Reduction of LDL-Cholesterol is Associated with a Reduction of Coronary Events

14. Research History on Plant Stanols and Sterols  Early 1950s to 1980s  Focus on sterols  Mid 1980s  Shift of focus from sterols to stanols  The 1990s  Focus on sterol and stanol esters as food ingredients  2000 to present  Low-fat food forms Plant Stanol Ester Containing Functional Food A New Option for Cholesterol Lowering

15. Lowering Cholesterol with Plant Stanol Ester Facts, Figures, Actions 10:30Klaus von Bergmann “Absorption, distribution, and elimination of plant sterols in humans” 11:00Helena Gylling “Plant stanol esters in human studies” 11:30Coffee 12:00Joghum Plat “Plant stanol and sterol esters - mechanisms and safety issues” 12:30Albert Wiegman “Children with familial hypercholesterolemia – Cardiovascular risk prevention” 13:00Discussion 13:30Lunch

16. HEARTS & MINDS Lowering Cholesterol with Plant Stanol Ester Closing Remarks Herbert Schuster, M.D., Ph.D. Humboldt University Berlin, Berlin, Germany Chairman

17. Plant Stanol Ester in Clinical Trials Summary (1) Over 40 clinical trials show that 2-3 grams of stanol ester lower... serum total cholesterol by about 10% serum LDL cholesterol by up to 15% serum plant sterols 30-50% does not affect HDL or TG

18. Plant Stanol Ester in Clinical Trials Summary (2) Stanol ester reduces serum cholesterol concentration... effectively long-term additive with other dietary changes additive with statins in diabetics in patients with metabolic syndrome in adults and children

19. Plant Stanol Ester are Included in Dyslipidemia Treatment Guidelines US National Cholesterol Education Program TLC diet Reference: JAMA: 2001;285:2486-2497. Reduced intake of cholesterol-raising nutrients LDL-lowering therapeutic options + Plant stanols/sterols (2 g per day) Viscous (soluble) fiber (10–25 g per day) International Atherosclerosis Society, 2003 International Lipid Information Bureau, in Dyslipidemia and Coronary Heart Disease, 3rd edition 2003, eds Gotto AM, Amarenco P, Assmann G, Carmena R, Davignon J, Fruchart JC, Kastelein JJP, Paoletti R, Tonkin A National guidelines, e.g. Käypä Hoito in Finland