FACTS, FIGURES AND ACTIONS LOWERING CHOLESTEROL WITH PLANT STANOL ESTER

Transcription

1 FACTS, FIGURES AND ACTIONS LOWERING CHOLESTEROL WITH PLANT STANOL ESTER

2 Editorial Although the death rate from cardiovascular disease (CVD) has decreased over the past years, CVD is still the most common cause of morbidity and mortality worldwide. The risk of developing CVD is strongly related to the blood cholesterol level. Numerous studies have established a direct relationship between cholesterol and the incidence of CVD. Meta analyses suggest, for every 1% decrease in cholesterol, there is a 2 % decrease in CVD. These results have been shown in patients treated with statins, niacin and bile acid resins, and with lifestyle changes. Whereas cholesterol lowering drugs are indicated in individuals with cholesterol measurements above certain target levels, lifestyle changes are recommended at any level of risk. Due to the fact that cholesterol lowering trials have demonstrated that the lower cholesterol the better, soluble plant stanols incorporated in foods have recently received considerable attention. Plant sterols and stanols, known since the early 1950s, are structurally analogous to cholesterol. They lower serum levels of total cholesterol and low density lipoprotein cholesterol by inhibiting the absorption of dietary cholesterol and the reabsorption of biliary cholesterol in human intestine. Combined with cholesterol lowering drugs and Therapeutic Lifestyle Changes (TLC) they add further cholesterol lowering effects. Functional foods containing plant stanols have the potential to become the basis of cholesterol management for all individuals at risk. Herbert Schuster, M.D. Professor of Medicine, Humboldt University Berlin BENECOL PLANT STANOL ESTER Reduces serum cholesterol effectively by reducing absorption of cholesterol Serum LDL cholesterol is reduced by up to 15 % and total cholesterol by up to 10 %; no effect on HDL cholesterol (1, 2) Also shown to reduce serum plant sterol concentrations (1) Effective in long term use (1) Complementary effect with statin therapy (3) and heart healthy lifestyles (4) Effective cholesterol lowering in diabetes (5) and familial hypercholesterolaemia (6) Effective regardless of gender or age (1, 7, 8) Excellent safety profile: no adverse events reported during the 11 years on the market or in clinical or toxicological studies Supported by more than 40 double blind, full clinical trials 1. Miettinen T et al. N Engl J Med 1995; 333: Miettinen T et al. Am J Clin Nutr 2000; 71: Blair SN et al. Am J Cardiol 2000; 86: Andersson A et al. Eur Heart J (Suppl 1999); 1: Gylling H and Miettinen T. Diabetologia 1994; 37: Vuorio AF et al. Arterioscler Thromb Vasc Biol 2000; 20: Gylling H et al. Circulation 1997; 96: Tammi A et al. J Pediatr 2000; 136:

3 CONTENT OVERVIEW TABLE OF CONTENTS DIET AND PREVENTION Introduction Mode of action Page 4 6 SAFETY Dual effect: Ketomäki et al EFFECTIVENESS Hypercholesterolaemic patients: Miettinen et al Children: Tammi et al Diabetic patients: Gylling et al Healthy diet: Andersson et al Statin therapy: Blair et al DIET AND PREVENTION General guidelines for lowering cholesterol: Cleeman et al Applications 22 3

4 INTRODUCTION PLANT STEROLS AND STANOLS IN HUMAN NUTRITION Ostlund RE. Annu. Rev. Nutr. 2002; 22: , Katan MB et al. Mayo Clinic Proc. 2003; 78: ABSTRACT Plant sterols are cholesterol-like molecules found in all plant foods, with the highest concentrations occurring in vegetable oils. Natural dietary intake of plant sterols varies between about mg /day and plant stanols between mg /day. Attempts to measure biological effects of plant sterols in feeding studies have been impeded by limited solubility of free sterols and stanols in both water and fat. Esterification of plant sterols and stanols with longchain fatty acids increases their fat solubility 10-fold and allows delivery of several grams daily in different foods. Increasing the amount of plant sterols and stanols in a variety of foods may be an important way of reducing population cholesterol levels and preventing coronary heart disease. Occurrence in natural diet Food Plant sterols [mg /100 g edible portion] Corn oil 952 Sunflower oil 725 Safflower oil 444 Soybean oil 221 Olive oil 176 Almonds 143 Beans 76 Corn 70 Wheat 69 Palm oil 49 Lettuce 38 Banana 16 Tomato 7 ABSORPTION AND SAFETY Plant sterols traditionally have been considered to be non-absorbable. In humans consuming solid food diets more than 90 % of sitosterol is recovered in the stool. Plant sterol absorption is quite low, particularly for stanols, which are absorbed over 10 times lower efficiency compared to equivalent sterols (see table below). Plasma levels of fat-soluble vitamins and other vegetable-derived compounds have been studied following plant sterol ingestion because of concern about the possibility of reduced absorption. Alpha- and betacarotene have been reported to be reduced slightly, although results have been inconsistent. However, no reduction in beta-carotene level was seen when plant sterols or plant stanols were consumed as part of a healthy diet containing fruits and vegetables. Absorption Absorption [%] Sitostanol 0.04 Sitosterol 0.51 Campestanol 0.16 Campesterol 1.90 Cholesterol 56.0

5 SUMMARY FROM RANDOMISED CLINICAL TRIALS Reduction in LDL cholesterol compared to sterol / stanol intake Reduction in LDL cholesterol [%] 20 Figure 1: Intake of 2 g /d reduced LDL cholesterol by 10 %. Katan et al Dose of sterol / stanol [g /d] LDL LOWERING A meta-analysis of 26 clinical trials showed that an intake of 2 g of stanols per day reduced LDL cholesterol by about 10 %. EDITOR S NOTE Following evidence from toxicological studies and numerous clinical trials, stanols are characterised as safe by authorities in several EU countries as well as by FDA in the USA. 5

6 MODE OF ACTION THE MOLECULAR MECHANISMS OF CHOLESTEROL LOWERING EFFECTS Figure 1: Similarities of cholesterol, sitosterol and sitostanol. MOLECULAR STRUCTURE Plant sterols are plant equivalents to cholesterol and have a closely similar molecular structure. According to their structure they can be divided into sterols and stanols. Stanols are a saturated subgroup of sterols. Plant sterols and stanols appear in everyday diets in concentrations too low to change blood cholesterol levels significantly. In the esterified form, stanols solubility in fat is increased and, in that form, they can be added to several kinds of foods. In the digestive tract, stanol ester is cleaved to stanols and fatty acids by pancreatic enzymes. Molecular structures Cholesterol MODE OF ACTION A TWO STEP MECHANISM The molecular mode of actions of stanols has been described in several preclinical and clinical trials and can be separated into two steps: Step 1: Cholesterol absorption occurs via the formation of micelles with bile acids. Stanols displace cholesterol from these micelles so that less cholesterol can be absorbed. Stanols need to be taken as part of a meal in order to be incorporated in the micelles. Step 2: In vitro studies have shown that stanols activate LXR alpha, LXR beta and ABC A1 transporter proteins. It is thus hypothesised that stanols work in enterocytes by activating the excretion of cholesterol back into the intestinal lumen. HO HO Sitosterol Sitostanol ONLY STANOLS HAVE SHOWN A SUSTAINED LONG-TERM EFFECT Only stanols are proven to retain their efficacy in longterm use. (Miettinen T et al. N Engl. J Med 1995; 333: ; Hendriks HF, et al. Eur J Clin Nutr 2003;57:681-92). It is hypothesised that this is due to the minimal absorption of stanols, and, consequently, their lack of effect on the bile acid metabolism (O'Neill FH, et al. Am J Cardiol 2005;96:29-36). EDITOR S NOTE 6 HO Plant stanol ester containing foods provide a safe and evidence-based cholesterol management option for everyone at any level of cardiovascular disease risk.

7 Mode of action a two step mechanism Step 1: Mixed micelles Replacement of cholesterol by stanol Figure 2: Best effect if consumed with meals. Emulsified fat Emulsified fat Stomach Cholesterol Stanol Triglyceride Monoacylglyceride Bile acid Mixed micelles Food digest Enterocyte Additional effects in combination with statins Statins lower cholesterol levels by inhibition of cholesterol synthesis. As a consequence, this leads to an increase of LDL receptors on liver cells and to a higher uptake of LDL cholesterol. In comparison, stanols reduce the intestinal absorption of cholesterol. Both these effects work together to deliver a combined therapy. Step 2: Activation of transporter protein leads to cholesterol / stanol excretion Intestinal lumen Mixed micelles Cholesterol excretion from the body Transporter protein Cholesterol Enterocytes Stanol 7

8 SAFETY RED CELL AND PLASMA PLANT STEROLS ARE RELATED DURING CONSUMPTION OF PLANT STANOL AND STEROL ESTER SPREADS IN CHILDREN WITH HYPERCHOLESTEROLEMIA Ketomäki AM et al. J Pediatr 2003; 142: RATIONALE There are some differences between stanol esters and sterol esters that have already been described (e.g. better long-term results of stanol ester Miettinen et al vs. Hendriks et al. 2003). PROTOCOL Randomisation n=23 The aim of the study was to investigate the differential effects of consuming plant sterol ester or plant stanol ester spreads on serum and red blood cell sterols in hypercholesterolaemic children. Plant stanol ester spread (stanol 2 g /d) Plant sterol ester spread (sterol 2 g /d) DESIGN Randomised, double blind, crossover study. Stanol 2 g /d. Ad libitum 5 weeks 5 weeks Ad libitum PATIENT POPULATION Inclusion criteria Age: 2-9 years Serum total cholesterol: >194 mg /dl Serum triglycerides <176 mg /dl Plant sterol ester spread (sterol 2 g /d) 5 weeks Evaluation n=23 Plant stanol ester spread (stanol 2 g /d) 8

9 RESULTS Changes in plasma lipids Change [%] Cholesterol LDL HDL TG Red cell percent changes of sterols to cholesterol ratio Change [%] Campesterol Sitosterol Avenasterol Figure 1: Significant LDL lowering. Stanol Sterol Figure 2: Consumption of stanol lowers sterol to cholesterol ratio of red cells. Stanol Sterol CONCLUSION Consumption of plant sterols increases and consumption of plant stanols decreases the ratio of plant sterols to cholesterol in red cells of hypercholesterolaemic children, proportionately to the respective changes in plasma. EDITOR S NOTE Because of their safety and lack of side effects, plant stanol ester enriched functional foods are optimal for cholesterol management in children with familial lipid disorders. 9

10 EFFECTIVENESS REDUCTION OF SERUM CHOLESTEROL WITH SITOSTANOL-ESTER MARGARINE IN A MILDLY HYPERCHOLESTEROLEMIC POPULATION Miettinen T et al. N engl. J Med 1995; 333: RATIONALE Clinical trials have shown that dietary plant sterols, especially sitostanol, reduce serum cholesterol by inhibiting cholesterol absorption. The cholesterol lowering effect may be increased when it is ingested in a soluble (ester) form. Miettinen et al. designed the present study to investigate the long-term tolerability and cholesterol lowering effect of margarine containing sitostanol ester in a mildly hypercholesterolaemic population sample. DESIGN Randomised, double blind, 1-year treatment. Sitostanol g /d. PATIENT POPULATION Inclusion / Exclusion criteria Serum cholesterol 216 mg /dl Triglyceride 265 mg /dl Age between 25 and 64 years Body mass index < 30 Stable medication for hypertension, diabetes, or coronary heart disease Absence of renal, alcohol, liver or thyroid problems Patient profile 153 patients 42 % male PROTOCOL Rapeseed oil margarine 24 g /d 6 weeks Randomisation Margarine without sitostanol (placebo) n=51 Margarine with sitostanol 2.6 g /d n = months Randomisation 10 Margarine with sitostanol 1.8 g /d n=51 Margarine with sitostanol 2.6 g /d n=51

11 RESULTS Effective LDL lowering LDL cholesterol [mg/dl] Months Figure 1: Long-term LDL lowering could be shown. Placebo 1.8 g Sitostanol 2.6 g Sitostanol Mean changes in serum lipid concentrations Figure 2: Difference [mg/dl] 95% CI p-value Total cholesterol to -32 < LDL cholesterol to -29 < HDL cholesterol to +3.1 Not significant Total triglycerides +5-7 to +19 Not significant HDL : LDL to Effective LDL lowering no influence to HDL concentration. CONCLUSION Daily sitostanol intake can lower LDL cholesterol at about 20 mg/dl in patients with mild hypercholesterolaemia A long lasting LDL lowering effect could be shown for at least 12 months No influence on HDL cholesterol No side effects EDITOR S NOTE Plant stanol ester enriched functional foods provide an additional option for cholesterol management and CVD risk reduction in individuals with low or moderate CVD risk. 11

12 EFFECTIVENESS PLANT STANOL ESTER MARGARINE LOWERS SERUM TOTAL AND LOW-DENSITY LIPOPROTEIN CHOLESTEROL CONCENTRATIONS OF HEALTHY CHILDREN: THE STRIP PROJECT Tammi A et al. J Pediatr 2000; 136: RATIONALE It has been shown that dietary plant stanol reduces serum cholesterol in different patient groups. So far, there has been no trial investigating stanol effects in children. This trial was initiated to investigate cholesterol lowering efficacy and safety of plant stanol ester margarine in healthy 6 year old children already consuming a low saturated fat, low cholesterol diet. PROTOCOL The STRIP project Randomisation (At the age of 7 months) n = 1062 Low fat Intervention group n = 540 Control group n = 552 DESIGN Placebo-controlled, double blind, randomised, crossover trial. Stanol 1.6 g /d. Plant stanol ester margarine study Randomisation (At the age of 6 years) n=81 PATIENT POPULATION Inclusion criteria All children were participants of the STRIP project (randomised, prospective trial aimed at decreasing exposure of the intervention children to known atherosclerosis risk factors). At the 6 year visit the children in the intervention group and their parents were asked whether they were interested in participating in this plant stanol ester margarine study. Exclusion criteria Diabetes Familial hypercholesterolaemia Plant stanol ester margarine (1.6 g stanol /d) Placebo margarine Placebo margarine 3 months 3 months 3 months Evaluation n=72 Placebo margarine Placebo margarine Plant stanol ester margarine (1.6 g stanol /d) 12

13 RESULTS Changes in lipid concentration by margarine intake above median Lowering [mg/dl] 0-0,4 Figure 1: Significant additional LDL lowering by 7.5 % ,7-10, Total cholesterol LDL cholesterol HDL cholesterol CONCLUSION EDITOR S NOTE Plant stanol ester margarine significantly diminishes serum total and low density lipoprotein cholesterol concentrations without adverse clinical effects in healthy children who already consume a low saturated fat, low cholesterol diet. The higher the LDL baseline, the greater the decreases in LDL cholesterol. Plant stanols have proven to be safe and tolerable in children above the age of 6 years. The cholesterol lowering effect is maintained even in combination with a low saturated fat, low cholesterol diet. 13

14 EFFECTIVENESS SERUM CHOLESTEROL AND CHOLESTEROL AND LIPOPROTEIN METABOLISM IN HYPERCHOLESTERO- LAEMIC NIDDM PATIENTS BEFORE AND DURING SITOSTANOL ESTER-MARGARINE TREATMENT Gylling H and Miettinen T. Diabetologia 1994: 37: RATIONALE Cardiovascular disease is the primary complication of diabetes. Although hypertriglyceridaemia and low HDL cholesterol are the typical findings in diabetic dyslipedaemia, also LDL cholesterol level should be kept low. The aim of this study was to investigate the suitability and the mode of action of a margarine with sitostanol ester for the hypolipidaemic treatment of hypercholesterolaemic NIDDM men. DESIGN Double blind, crossover. Sitostanol 3 g /d. PATIENT POPULATION 11 NIDDM men (non insulin dependent diabetes mellitus) Mean age 57.8 ±1.9 (SEM) years No microalbuminuria, retino- or neuropathia or hepatic or gastrointestinal diseases PROTOCOL Margarine without sitostanol (placebo) n=5 Margarine with sitostanol (3 g sitostanol /d) n=5 Normal diet Randomisation 6 weeks 6 weeks Evaluation n=11 4 weeks Margarine with sitostanol (3 g sitostanol /d) n=6 Margarine without sitostanol (placebo) n=6 14

15 RESULTS Changes of lipid concentration by dietary sitostanol Change [%] Total cholesterol LDL cholesterol HDL cholesterol Figure 1: Effective lowering of LDL in NIDDM men. CONCLUSION Serum total, VLDL and LDL cholesterol were significantly lowered by 6 ± 2, 12 ± 6 and 9±3% HDL cholesterol was 11±4% higher following sitostanol ester treatment Cholesterol absorption efficiency was markedly reduced following sitostanol ester treatment EDITOR S NOTE For patients with diabetes and cardiovascular disease, and a corresponding target LDL cholesterol level below 70 mg /dl, plant stanol ester enriched functional foods provide the option to go as low as possible with their cholesterol levels in combination with drug treatment. 15

16 EFFECTIVENESS CHOLESTEROL-LOWERING EFFECTS OF A STANOL-ESTER CONTAINING LOW-FAT MARGARINE USED IN CONJUNCTION WITH A STRICT LIPID-LOWERING DIET Andersson A et al. Eur Heart J Supplements 1999; 1 (suppl S): S80 - S90 RATIONALE Therapeutic lifestyle changes like low cholesterol diet are a recommended way to reduce chronic heart disease risk factors in patients with mild hypercholesterolaemia. The aim of the study was to investigate a possible additional cholesterol lowering effect when a plant stanol ester containing margarine was added to a cholesterol lowering diet. DESIGN Controlled and randomised study. Stanol 2 g /d. PROTOCOL PATIENT POPULATION Inclusion criteria Serum cholesterol >194 mg /dl LDL >116 mg /dl Exclusion criteria Serum cholesterol > 330 mg /dl Body mass index > 30 During the 3 months before the study Body weight changes of > 4 kg Treatment with lipid lowering drugs Specific diets or food allergies that would interfere with the test diet Diseases affecting lipid metabolism (renal, thyroid or liver disorders, diabetes mellitus on treatment or increased fasting blood glucose level) Alcohol overconsumption Persons who, because of language barriers, were considered unable to adhere to the protocol Usual diet + control margarine n=68 4 weeks Randomisation Usual diet + test margarine (stanol 2 g /d) n=21 Test diet + control margarine n=21 8 weeks Evaluation n=61 Test diet + test margarine (stanol 2 g /d) n=19 16

17 RESULTS Effects of a low fat stanol ester containing margarine on serum lipid concentrations Change [%] % -9 % 0% -4 % -7 % -9 % Figure 1: Combination of plant stanol and a strict lipid lowering diet showed a significant additional LDL lowering effect over the strict diet alone (p = ). Usual diet + test margarine Test diet + control margarine Test diet + test margarine % -12 % -12 % -13 % -12 % % Total cholesterol LDL cholesterol HDL cholesterol LDL / HDL cholesterol CONCLUSION Dietary plant stanol esters seem to be a safe and effective dietary tool as part of a cholesterol lowering diet, to lower elevated cholesterol levels also on a population basis. EDITOR S NOTE Plant stanol ester containing functional foods provide additional cholesterol lowering effects on top of traditional cholesterol lowering diet. 17

18 EFFECTIVENESS INCREMENTAL REDUCTION OF SERUM TOTAL CHOLESTEROL AND LOW-DENSITY LIPOPROTEIN CHOLESTEROL WITH THE ADDITION OF PLANT STANOL ESTER-CONTAINING SPREAD TO STATIN THERAPY Blair SN et al. Am J Cardiol 2000 Jul 1; 86 (1): RATIONALE Statins block the synthesis of cholesterol, whereas plant stanol esters block the absorption of cholesterol. Therefore, greater reductions in serum cholesterol would appear likely when plant stanol esters and statins are administered concomitantly. To test this hypothesis, Blair et al. investigated the efficacy and safety of the combined therapy of a statin and a spread containing plant stanol esters in lowering serum concentrations of total and LDL cholesterol. DESIGN Eight weeks, randomised, double blind and placebo-controlled (vegetable oil margarine) trial. Plant stanol ester 5.1 g /d (3 g stanol /d). PATIENT POPULATION Inclusion criteria Age 20 years LDL cholesterol 130 mg /dl Triglyceride 350 mg /dl Stable regime of atorvastatin calcium, pravastatin sodium, simvastatin, or lovastatin, with no change in dosage or frequency of administration for a minimum of 90 days before study entry Exclusion criteria Gastrointestinal disorders or previous gastrointestinal surgery History of myocardial infarction or stroke within 3 months before study entry Diabetes requiring insulin use Concurrent use of other cholesterol-reducing products within 30 days before enrolment PROTOCOL Stable statin dose n = days Randomisation 18 Placebo (Vegetable oil margarine) n=84 Drop outs n=12 Completed 8 week examination n=72 Plant stanol ester 5.1 g /d (3 g stanol/d) n=83 Drop outs n=14 Completed 8 week examination n=69

19 RESULTS Additional LDL change from baseline LDL change [%] Figure 1: Additional LDL lowering for the combination of statin + stanol could be shown. Placebo Stanol Weeks CONCLUSION An additional LDL lowering effect could be shown for the combination of statin + stanol No influence on HDL concentration EDITOR S NOTE The cholesterol lowering effect, provided by plant stanol ester enriched functional foods, provides an additional effect in combination with statin therapy, and is well tolerated and safe. 19

20 DIET AND PREVENTION EXECUTIVE SUMMARY OF THE THIRD REPORT OF THE NCEP EXPERT PANEL ON DETECTION, E VA L U ATION, AND TREATMENT OF HIGH BLOOD CHOLESTEROL IN ADULTS (Adult Treatment Panel III) Cleeman JL et al. JAMA May 16; 285 (19): Diet, Nutrition, and the Prevention of Chronic Diseases. Geneva, 2002 (WHO Technical Report Series, 916) PREVENTION OF CHD LDL cholesterol is a major cause of coro n a ry heart diseas e s (CHD). The treatment goal to prevent CHD by reducing LDL cholesterol levels is the lowe r, the better. For CHD prevention the National Cholesterol Education Program (NCEP) Ex p e rt Panel re c o m- mends a LDL lowering therapy depending on individual risk assessment. Step 1: Determine individual risk To estimate the 10 year CHD risk determine the Framingham point score by adding the points from the tables age, total cholesterol, HDL cholesterol, smoking and blood pressure. Step 2: Determine LDL lowering indication The indication for therapeutic lifestyle changes (TLC) or drug therapy depends on 10 year CHD risk and on LDL cholesterol levels and is shown in the last table. Plant sterols and stanols as part of TLC are recommended by US National Cholesterol Education Program, International Atherosclerosis Society, International Lipid Information Bureau and WHO. Age Points Age [y] Men Women HDL cholesterol Points HDL [mg /dl] Men Women < Total cholesterol Points 20-39y 40-49y 50-59y 60-69y 70-79y Total cholesterol [mg /dl] Men Women Men Women Men Women Men Women Men Women <

21 International Atherosclerosis Society, 2003, as accessed June 26th, 2006 at International Lipid Information Bureau, in Dyslipidemia and Coronary Heart Disease, 3rd edition 2003, eds Gotto AM et al., ISBN Smoking Points Age 20-39y 40-49y 50-59y 60-69y 70-79y Men Women Men Women Men Women Men Women Men Women Nonsmoker Smoker Blood pressure Points Systolic BP [mmhg ] < Men Women Men Women Men Women Men Women Men Women Untreated Treated Result: 10 year CHD risk Points Men Point total < year CHD risk [%] < Women Point total < year CHD risk [%] < Indications for TLC or drug therapy Risk category LDL goal Indication for TLC Indication for drug therapy [mg /dl] [mg /dl] [mg /dl] CHD or CHD risk equivalents (10 year risk > 20 %) < ( : drug optional) 2 + risk factors (10 year risk 20 %) < year risk %: year risk <10 %: risk factor < ( : drug optional) 21

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