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EXPERT PANEL WORKSHOP SYSTEMATIC SCIENTIFIC LITERATURE REVIEW: BEANS [PHASEOLUS VULGARIS] AND CHOLESTEROL- LOWERING PRESENTED BY: RACHEL REBRY, M.SC. ASSOCIATE DIRECTOR, NUTRITION AND NUTRACEUTICAL RESEARCH DIVISION NUTRASOURCE DIAGNOSTICS INC. JULY 31, 2013 WWW.NUTRASOURCE.CA

Presented to: July 31, 2013

SESSION OVERVIEW NDI S SYSTEMATIC SCIENTIFIC LITERATURE REVIEW: BEANS AND CHOLESTEROL-LOWERING CHARACTERIZATION OF THE FOOD (BEANS) CHARACTERIZATION OF THE HEALTH EFFECT (CHOLESTEROL-LOWERING) EVALUATION OF CANADIAN AND U.S. HEALTH CONCLUSIONS CLAIM SUBSTANTIATION

CHARACTERIZATION OF THE FOOD BEANS

CHARACTERIZATION OF THE FOOD The bean (Phaseolus vulgaris species) is an edible pulse and is part of the legume (Fabaceae) family Beans have been reported to be beneficial for: Heart Disease Diabetes Neural Tube Defects Colon and Cervical Cancer Satiety Beans have many beneficial bioactive components that contribute to their health attributes Agriculture and Agri-Food Canada, 2007

CHARACTERIZATION OF THE FOOD Phytochemicals Complex Carbohydrates Soluble & Insoluble Fibre Antioxidants Gluten Free Beneficial Components of Beans Resistant/ Slowly Digested Starch Vegetable Protein Minerals Iron Calcium Magnesium Vitamins Folate Little to no fat Agriculture and Agri-Food Canada, 2007; Pulse Canada, 2012

CHARACTERIZATION OF THE FOOD Food Product Applications: Whole Beans Soups Salads Ethnic Cuisine (Mexican, Caribbean) Tomato sauces Ready-to-eat meals Vegetarian products Bean Flours Gluten-free applications Pasta Breads, buns, baked goods Crackers and cookies Extruded and puffed snack foods Bean Flakes Nutrition bars Breakfast cereals Bread, buns, cookies and baked goods Soups Casseroles Pilafs Pulse Canada, 2008

CHARACTERIZATION OF THE FOOD Previous Findings: Supplementing the diet with beans can reduce serum LDL and total cholesterol concentrations There is evidence to suggest that pulse consumption (including beans) can decrease the risk for coronary heart disease (CHD) Beneficial effects have been noted in both normal and hypercholesterolemic populations Pulse Canada, 2008; Anderson et al., 1984; Anderson & Major, 2002; Winham & Hutchins 2007

CHARACTERIZATION OF THE FOOD CANADIAN CONSUMPTION: Canadian Community Health Survey (2004): 13.1% of Canadians reported consuming dry beans, peas or lentils on any given day Bean dishes made up two-thirds of food sources of pulse products in the adult Canadian diet Highest proportion of pulse consumers were 51-70 years of age Self-identified Asian-Canadians were 3.6x more likely to be pulse consumers vs. selfidentified Caucasians Mudryj et al., 2012

CHARACTERIZATION OF THE FOOD CANADIAN CONSUMPTION: Ipsos Reid Report (2010): 2 in 3 (66%) Canadians reported consuming beans in the past 6 months Consumption of beans, peas and lentils is significantly higher among Canadians who have a household member with heart disease, diabetes or high blood cholesterol Canned whole beans (76%) are the clear leader when it comes to forms purchased, compared to dried (54%) and soups (45%) followed by dips or spreads (29%) Ipsos Reid, 2010

Mitchell et al., 2009; Lucier et al., 2000 CHARACTERIZATION OF THE FOOD AMERICAN CONSUMPTION: 7.9% of the U.S. population from 1999-2002 consumed beans, peas, or lentils on any given day vs. 14% of the U.S. population consumed at least one food containing dry cooked beans in 1994-1996 Main sources of beans: Pinto beans, baked beans, chili and other Mexican or Hispanic dishes

CHARACTERIZATION OF THE FOOD Dietary Intake: Canada s Food Guide recommends 2-3 servings of Meat and Alternatives each day [1 serving = ¾ cup] Emphasis has been placed on consumption of beans, lentils and tofu The United States Department of Agriculture (USDA) Beans are an excellent source of plant protein, iron and zinc Serving size is equal to approximately ½ cup Can be part of the vegetable group or protein group 2.5 to 3 cups of vegetables recommended daily 5 to 6 ounce protein equivalents recommended daily Health Canada, 2007; CFIA, 2012; USDA

CHARACTERIZATION OF THE HEALTH EFFECT CHOLESTEROL-LOWERING

CHARACTERIZATION OF THE HEALTH EFFECT High Blood Cholesterol: 3 major classes of lipoproteins that make up serum total cholesterol (TC) include: Low density lipoprotein (LDL) bad High density lipoprotein (HDL) good Very low density lipoprotein (VLDL) bad High blood cholesterol is one of the major risk factors for heart disease Too much cholesterol in the blood can lead to: Chest pain (Angina) Heart attack Coronary Heart Disease (CHD) Atherosclerosis Stroke NCEP, 2002; NIH, 2005

CHARACTERIZATION OF THE HEALTH EFFECT Classification of Total Cholesterol and LDL Cholesterol: Total Cholesterol (mg/dl) LDL Cholesterol (mg/dl) <200 Desirable <100 Optimal 200-239 Borderline High 100-129 Near Optimal/Above Optimal 240 High 130-159 Borderline High TC and LDL-C 160-189 High 190 Very High Risk for Heart Disease NCEP, 2002

CHARACTERIZATION OF THE HEALTH EFFECT Healthy Levels of Cholesterol in Blood: <135.3 mg/dl (NCEP near optimal) <200 mg/dl (NCEP desirable) Type of Cholesterol LDL Cholesterol (bad) HDL Cholesterol (good) Total Cholesterol Ratio of Total Cholesterol to HDL Cholesterol Healthy Concentration < 3.5 mmol/l >1.0 mmol/l males > 1.3 mmol/l females < 4.5 mmol/l (6 to 19 year olds) < 5.2 mmol/l (20 to 79 year olds) < 5.0 Statistics Canada, 2012

CHARACTERIZATION OF THE HEALTH EFFECT Prevalence in Canada: 40% of Canadian adults have high blood cholesterol levels As many as 10 million Canadian adults have a cholesterol level higher than the recommended target Additionally, 9 out of 10 Canadians have at least one risk factor for heart disease and stroke (which includes high blood cholesterol) Heart and Stroke Foundation, 2013; Statistics Canada, 2012; National Institute of Health and Human Sciences, 2005

CHARACTERIZATION OF THE HEALTH EFFECT Prevalence in the United States: Heart disease is the leading cause of death in the United States 1 in every 6 adult Americans has high blood cholesterol An estimated 31.9 million adults have total serum cholesterol levels 240 mg/dl [HIGH] In 2010, approximately 71 million adults had LDL-C 130 mg/dl [BORDERLINE-HIGH to VERY HIGH] In 2007-2010, approximately 5.6% of adult Americans had undiagnosed hypercholesterolemia Hoyert and Xu, 2012; CDC, 2012; Go et al., 2013

CHARACTERIZATION OF THE HEALTH EFFECT Total Cholesterol [TC] HDL Cholesterol [HDL-C] Biomarkers of Cholesterol- Lowering LDL Cholesterol [LDL-C] Triglycerides [TG]

SCOPE OF WORK In 2012-2013, Nutrasource Diagnostics Inc. conducted a systematic literature review investigating the effects of beans on cholesterol lowering This review and evaluation was performed by NDI on behalf of the Ontario Bean Producers Marketing Board/Ontario Bean Growers and Pulse Canada

SCOPE OF WORK Purpose of the Systematic Scientific Literature Review: To provide a synopsis of the body of evidence on beans and cholesterol lowering Based on the body of evidence, to determine the potential relationship between bean consumption and cholesterol lowering

SCOPE OF WORK Purpose of the Systematic Scientific Literature Review: To indicate the potential validity of a new therapeutic health claim, based on Health Canada s Guidance Document for Preparing a Submission for Food Health Claims (2009) and The U.S. FDA s Guidance for Industry: Evidence-Based Review System for the Scientific Evaluation of Health Claims Final (2009)

SCOPE OF WORK

SCOPE OF WORK The evaluation process involves a series of steps to assess scientific studies and other data, eliminate those from which no scientific conclusions about the substance/disease relationship can be drawn, rate the remaining studies for methodological quality, quantity of evidence for and against the claim (taking into account the numbers of various types of studies and study sample sizes), relevance to the U.S. population or target subgroup, replication of study results supporting the proposed claim, and overall consistency of the evidence.

Similarities between health claim guidance in Canada and the U.S. Food/constituent should be characterized sufficiently Food/constituent being studied is the same as the food/constituent for which the claim is being sought o Physical and chemical composition o Molecular form o Matrix o Dose Biomarkers of exposure and outcome must have biological and methodological validity Literature search is comprehensive, transparent and reproducible Musa-Veloso, K (Cantox Health Sciences International), 2009

Similarities between health claim guidance in Canada and the U.S. Scientific support is derived from clinical intervention studies o Prospective cohort studies can be supportive evidence Clinical studies are of high methodological quality (RCTs) Relevant populations used Magnitude of effect is statistically significant (p<0.05) Health effect is physiologically relevant Health claim wording supports an understanding of the relevance of clinical evidence and is clear and unambiguous Musa-Veloso, K (Cantox Health Sciences International), 2009

DEFINE THE SEARCH STRATEGY Keyword Combinations: Food Bean OR Beans OR Dry Bean OR Phaseolus vulgaris Legumes OR leguminous seeds OR legumen Final Health Effect CVD OR cardiovascular disease, CHD OR coronary heart disease, CAD OR coronary artery disease, Myocardial ischemia, Myocardial infarction OR heart attack, Atherosclerosis, Hyperlipidemia, Hypercholesterolemia, Dyslipidemia Biomarker of Health Effect Cholesterol OR cholesterol reduction, Lipids OR blood lipids, Total cholesterol OR TC, Triglycerides OR triacylglycerol OR TG, LDL cholesterol OR LDL-C, HDL cholesterol OR HDL-C

DEFINE THE SEARCH STRATEGY Inclusion/Exclusion Criteria: Source Published, peer reviewed journals Report Type - Full-length Article/Study (Original human research Language - English Publication Year 1980 to date of search Treatment beans were quantified, and administered independent of other nutritional/pharmaceutical interventions Control study is appropriately controlled Route of Exposure - Oral Age of Participants - >9 years of age, to be as inclusive as possible to optimize the breadth and depth of literature considered Statistical Significance must be reported Duration - 3 weeks Health Effect TC and/or LDL-C value reported Population Health Status generally healthy, non-diseased individuals (no cholesterol-lowering meds)

LITERATURE RETRIEVAL/FILTERING PubMED, ProQuest, Hand-Searching 4142 2478 PubMED 1658 ProQuest 6 Hand-Searched 93 Full-Text Articles Reviewed 16 Intervention Publications Accepted 7 Unique Intervention Publications (8 treatment arms) Title and Abstract Filtering : 4049 titles excluded Full-Text Filtering : 77 fulltext articles excluded (3 of which were considered as supporting references) Duplicates between PubMED, ProQuest and Hand Searching: 9

LITERATURE RETRIEVAL/FILTERING Included Publications: Article No. Publication No. of Comparisons Description of Treatment Arms 1 Anderson et al., 1990 1 Type IIa or IIb hyperlipoproteinemic subjects; 120-162 g beans [as pork and beans in tomato sauce] with metabolic diet designed to resemble a typical American diet. 2 Cobiac et al., 1990 1 Mildly hypercholesterolemic subjects; 440 g/d baked beans [cooked and canned] with usual diet [containing 19.9 g nonstarch polysaccharides] 3 Finley et al., 2007 2 Healthy subjects; ½ cup [130 g/d] canned cooked pinto beans with self-selected diets Pre-Metabolic Syndrome subjects; ½ cup [130 g/d] canned cooked pinto beans with self-selected diets 4 Mackay and Ball, 1992 1 Usual diet with the addition of 80 g/d cooked beans [pinto, haricot and kidney with 29 g of fiber] 5 Oosthuizen et al., 2000 1 Hyperlipidemic subjects; 110 g/d extruded dry beans [15 g total non-starch polysaccharides] in the form of corn savoury bread, chocolate cake, banana bread and raisin muffins into their usual diets 6 Winham and Hutchins, 2007 1 Hypercholesterolemic subjects; ½ cup [130 g/d] serving of vegetarian baked beans as well as the brine or liquid they were packaged in as part of their usual diet 7 Winham et al., 2007 1 Mildly insulin resistant subjects; ½ cup canned pinto beans [130 g/d] as well as the brine or liquid the beans were packaged in as part of their usual diet 8 Total Number of Treatment Arms

QUALITY APPRAISAL: CANADA Health Canada s Quality Appraisal Tool considers items which could potentially bias study quality (total of 15 points) Low quality study = Score 7 High quality study = Score 8 Inclusion/exclusion criteria Group allocation Blinding Attrition Exposure/intervention Health effect Statistical analysis Potential confounders

QUALITY APPRAISAL: US FDA The Quality Appraisal Tool development for the US health claim investigation was developed based on FDA written guidance (total of 14 points) Low quality study= Score 5 Moderate quality study = Score 6 to 9 High quality study = Score 10 to 14 Randomization Blinding Inclusion/Exclusion Criteria Potential confounders Attrition Assessment of compliance Statistical analysis Measurement of disease incidence/surrogate endpoints of disease risk

QUALITY APPRAISAL Health Canada 6/8 were of high quality (score 8/15) Anderson et al. (1990); Cobiac et al. (1990); Mackay & Ball, 1992; Oosthuizen et al. (2000); Winham & Hutchins (2007), Winham et al. (2007) 2/8 were of lower quality (score 7/15) Finley et al. x 2 (2007) U.S. FDA 1/8 was of high quality (score 10 to 14/14) Winham et al., 2007 7/8 were of moderate quality (score 6 to 9/14) Anderson et al. (1990); Cobiac et al. (1990); Finley et al. x2 (2007); Mackay & Ball, 1992; Oosthuizen et al. (2000); Winham & Hutchins (2007)

CONSISTENCY OF EFFECT Considers all studies with regards to: Direction of effect [favourable or unfavourable] Study quality Statistical significance of the effect is not considered at this point Consistency ratings: High [ 75%] Moderate [60-74%] Low [<60%]

CONSISTENCY OF EFFECT HEALTH CANADA Following the Consumption of Beans: TC Highly consistent beneficial effect Support by 83.3% of the high quality studies LDL-C Highly consistent beneficial effect Supported by 83.3% of the high quality studies HDL-C Low consistency for this beneficial effect Supported by 0% of the high quality studies TG Moderately consistent beneficial effect Supported by 66.7% of the high quality studies

CONSISTENCY OF EFFECT U.S. FDA Following the Consumption of Beans: TC Highly consistent beneficial effect Support by 87.5% of the moderate and highquality studies LDL -C Highly consistent beneficial effect Supported by 87.5% of the moderate and high-quality studies HDL-C Low consistency for this beneficial effect Supported by 0% of the moderate and highquality studies TG Low consistency for this beneficial effect Supported by 50% of the moderate and high-quality studies

STRENGTH OF ASSOCIATION Determining the Strength of Association: Assess the strength of association between the food and health outcome Consideration for the proportion of studies which showed statistical significance at p<0.05 Strength of Association Ratings: High [ 75%] Moderate [60-74%] Low [<60%]

STRENGTH OF ASSOCIATION HEALTH CANADA Following the Consumption of Beans: TC LOW: 50% of high quality studies demonstrated a statistically significant favourable effect Magnitude of Effect: -4% to -10.4% reduction LDL-C LOW: 33.3% of high quality studies demonstrated a statistically significant favourable effect Magnitude of effect: -7% to -10.96% reduction HDL-C LOW: 0% of high quality studies demonstrated a statistically significant favourable effect Some studies showed statistically significant decreases TGs LOW: 16.7% of high quality studies demonstrated a statistically significant favourable effect

STRENGTH OF ASSOCIATION U.S. FDA Following the Consumption of Beans: TC MODERATE: 62.5% of moderate and high-quality studies demonstrated a statistically significant favourable effect Magnitude of Effect: -4% to -10.4% reduction LDL-C LOW: 50% of moderate and high-quality studies demonstrated a statistically significant favourable effect Magnitude of effect: -7% to -10.96% reduction HDL-C LOW: 0% of moderate and high-quality studies demonstrated a statistically significant favourable effect TGs LOW: 12.5% of moderate and high-quality studies demonstrated a statistically significant favourable effect

EVALUATION OF HEALTH CLAIM VALIDITY Bean consumption appears to have consistent beneficial effects on total and LDL-C, but only a moderate to low beneficial effect on triglycerides and HDL-C The strength of association between bean consumption and cholesterol-lowering, when considering statistical significance is not as certain However, of the properly powered included studies, 80% showed statistically significant reductions in TC and 60% saw significant reductions in LDL-C Meta-analysis of the current data may help strengthen our understanding of the data

MINIMUM EFFECTIVE INTAKE Statistically significant beneficial effects have been demonstrated in a some of the studies investigating bean consumption and cholesterol lowering Range of daily intake: 80g cooked beans (No SS effect) 440 g canned beans (No SS effect)

MINIMUM EFFECTIVE INTAKE What was the lowest dose of beans administered in included studies associated with a significant reduction in both total cholesterol and LDL-C? 130 grams (cooked or canned) beans per day

FEASIBILITY OF CONSUMPTION MINIMUM EFFECTIVE INTAKE - CANADA RECAP on Dietary Intake: Canada s Food Guide recommends 2-3 servings of Meat and Alternatives each day [1 serving = ¾ cup] Emphasis has been placed on consumption of beans, lentils and tofu Health Canada, 2007

FEASIBILITY OF CONSUMPTION MINIMUM EFFECTIVE INTAKE - CANADA Bean Product/Type Amount of Food Required to Make 1 Food Guide Serving (3/4 cup; 175 ml) Beans, kidney, all types, boiled 131 g Beans, navy, boiled 135 g Beans, white, boiled 132 g Beans, pinto, boiled 126 g Beans, black turtle, boiled 137 g Beans, cranberry (roman), boiled 131 g Beans, pink, boiled 123 g Average Amount: 130.7 g # of Food Guide Servings Required: 1 Canadian Nutrient File Database, 2012; Health Canada, 2008

FEASIBILITY OF CONSUMPTION MINIMUM EFFECTIVE INTAKE U.S. Dietary intake: The United States Department of Agriculture (USDA) Beans are an excellent source of plant protein, iron and zinc ½ cup serving is equal to 130 g (as per included studies)

FEASIBILITY OF CONSUMPTION MINIMUM EFFECTIVE INTAKE UNITED STATES Bean Product/Type Beans (black turtle, mature seeds, canned) Beans (black turtle, mature seeds, cooked, boiled, without salt) Beans (kidney, all types, mature seeds, canned) Beans (kidney, all types, mature seeds, cooked, boiled, without salt) Beans (navy, mature seeds, canned) Beans (navy, mature seeds, cooked, boiled without salt) Beans (pinto, mature seeds, canned, drained solids, rinsed) Beans (pinto, mature seeds, cooked, boiled, without salt) # of ½ cup servings or amount of food required to obtain average Minimum Effective Dosage (130 g cooked/canned beans) 1.08 servings [120.0g] 1.41 servings [92.5g] 1.02 servings [128.0g] 1.47 servings [88.5g] 1.01 servings [131.0g] 1.43 servings [91.0g] 1.54 servings [84.5g] 1.52 servings [85.5g] Beans (white, mature seeds, canned) 1.01 servings [131 g] Beans (white, mature seeds, cooked, boiled, without salt) USDA Nutrient Data Laboratory, 2011 1.45 servings [89.5g] Average Number of ½ c. servings Needed: 1.3 or 2/3 c.

FEASIBILITY OF CONSUMPTION MINIMUM EFFECTIVE INTAKE What are the estimated changes in usual dietary patterns based on this intake of beans? Dietary Fibre Thiamin Saturated Fat and Cholesterol Magnesium Iron Vegetable Protein Folate Health Canada, 2010

GENERALIZABILITY TO THE TARGET POPULATION Half (4/8) of the intervention studies used hypercholesterolemic participants with total cholesterol concentrations ranging from 4.86 to 10.91 mmol/l and LDL-C concentrations ranging from 2.84 to 5.03 mmol/l Two intervention studies used borderline-mildly hypercholesterolemic participants with total cholesterol concentrations ranging from 4.2 to 7.4 mmol/l and LDL-C concentrations ranging from 2.1 to 4.8 mmol/l One intervention study used healthy and pre-metabolic syndrome participants with total cholesterol concentrations ranging from 3.1 to 5.8 mmol/l

GENERALIZABILITY TO THE TARGET POPULATION Applicable because Raised total cholesterol in 2008 (ages 25+) 5 mmol/l = 56.2% High total blood cholesterol in 2009 (ages 20+) 6.2 mmol/l = 13.1% 9.5% of the Canadian population are being treated with lipidlowering drug therapy Among the adult Canadian population who are not being treated with lipid-lowering medication: 33.8% have optimal LDl-C 50.7% have sub-optimal LDL-C 15.5% have uncontrolled high or very high LDL-C levels PHAC, 2011; WHO, 2013

GENERALIZABILITY TO THE TARGET POPULATION Applicable because 98.9 million Americans age 20+ have TC levels of 200 mg/dl or higher [borderline high to high] Among Americans 20+, the following have an LDL-C level of 130 mg/dl or higher [borderline high to very high]: Non-hispanic whites, 30.1% of men and 29.3% of women Non-hispanic blacks, 33.1% of men and 31.2% of women Mexican Americans, 39.9% of men and 30.4% of women The percentage of adults using cholesterol-lowering medication increased from 5% to 23% from the late 1980 s through 2007-2010 WHO, 2013; AHA, 2013; Kuklina et al., 2013

PHYSIOLOGICAL MEANINGFULNESS OF THE HEALTH EFFECT Biomarker Magnitude of Effect (Range) Total Cholesterol -4.0% to -10.4% LDL Cholesterol -7.0% to -10.96% 1% LDL-C 1% CHD Risk 1% TC 2% CHD Risk 7-21% in CHD Risk

Anderson and Major, 2002; Bazzano et al., 2011 CONCLUSIONS Controlling and/or lowering TC and LDL-C concentrations over time will have significant long-term health implications for adults with respect to coronary heart disease prevention As with any food-health relationship, maximum benefit may be obtained within the realm of an overall healthy diet and lifestyle

CONCLUSIONS Considering the high percentages of Canadians and Americans with high total and LDL-C levels It may be prudent to recommend consuming 130 g of cooked or canned beans to Canadians and Americans to help lower TC and LDL-C levels and help promote a healthy blood lipid profile Pending further research to address gaps in knowledge and build the body of high-quality evidence demonstrating statistically significant reductions in TC and LDL-C concentrations

CONCLUSIONS A therapeutic health claim and health claim for beans and cholesterol-lowering in Canada and the U.S., respectively, is promising

THANK YOU! NUTRITIONAL AND NUTRACEUTICAL RESEARCH DIVISION NUTRASOURCE DIAGNOSTICS INC. www.nutrasource.ca