2020

SCIENTIFIC UPDATE ON -BASED EATING AND CARDIOMETABOLIC HEALTH

Authors: Hana Kahleova, MD, PhD; Nerea Becerra-Tomas, RD, PhD; Sonia Blanco Mejia, MD, MSc; Andrea J Glenn, MSc, RD; Stephanie De Vriese, PhD; David JA Jenkins, MD, PhD; Cyril WC Kendall PhD; Jordi Salas-Salvadó, MD, PhD; John L Sievenpiper MD, PhD

September 2020

Affiliations of the authors:

Hana Kahleova 1, MD, PhD; Nerea Becerra-Tomas 2-3, RD, PhD; Sonia Blanco Mejia 4-5, MD, MSc; Andrea J Glenn 4-5, MSc, RD; Stephanie De Vriese 6, PhD; David JA Jenkins 4-5, MD, PhD; Cyril WC Kendall 4-5 PhD; Jordi Salas-Salvadó 2-3, MD, PhD; John L Sievenpiper 4-5 MD, PhD

1 Department of Medicine, Physicians Committee for Responsible Medicine, Washington, DC, USA. 2 Department of Biochemistry and Biotechnology, Human Unit, Pere Virgili Institute for Health Research (IISPV), University Hospital of Sant Joan de Reus, Rovira i Virgili University, Reus, Spain 3 Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y la Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain 4 St. Michael's Hospital, Toronto, Canada 5 Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Canada 6 Foundation; Ghent, Belgium

This review is fully supported by the Scientific Advisory Committee of the Alpro Foundation: Harry Aiking (VU University Amsterdam); Anna Arnoldi (University Milano); Christine Debeuf (Alpro); Peter Clarys (Vrije Universiteit Brussel); Helmut Heseker (University Paderborn); Sander Kersten (University Wageningen); Ian Rowland (University Reading); Cesare Sirtori (University Milano); Bregt Uyttenhove (Alpro) and Kurt Widhalm (University Vienna)

Date: September 2020

2 CONTENT

Global Health Burden of Cardiometabolic Disease...... 5 Cardiovascular Disease ...... 6 Type 2 Diabetes ...... 8 Stroke ...... 8 Metabolic Syndrome ...... 8 Non-Alcoholic Fatty Liver Disease ...... 8 Types of Plant-Based Dietary patterns ...... 11 Healthy and Unhealthy Plant-Based Index ...... 13 Pro-Vegetarian Food Pattern ...... 14 Cardiometabolic Risk Factors ...... 15 Blood Pressure ...... 16 Lipid Profile ...... 17 Inflammation and Endothelial Function ...... 17 /Overweight/ Adiposity ...... 18 Glucose Metabolism ...... 19 Non-Alcoholic Fatty Liver Disease ...... 20 Plant Components and Food Groups ...... 21 Nuts ...... 22 Soy ...... 24 ...... 27 Whole and Fiber ...... 29 and ...... 31 Different Plant-Based Food Patterns ...... 33 Portfolio Diet ...... 34 Portfolio Diet and Cardiometabolic Risk Factors ...... 34 Portfolio Diet and Cardiometabolic Diseases ...... 38 ...... 38 Mediterranean Diet and Cardiometabolic Risk Factors ...... 39 Mediterranean Diet and Cardiometabolic Diseases ...... 40 Nordic Diet ...... 43

3 Nordic Diet and Cardiometabolic Risk Factors ...... 43 Nordic Diet and Cardiometabolic Diseases ...... 44 Vegetarian and Vegan Diets ...... 45 Vegetarian Diets and Cardiometabolic Diseases ...... 45 Vegetarian Diets and Cardiometabolic Risk Factors ...... 46 Conclusion ...... 47

Plant-Based Food Patterns have positive effects on cardiometabolic diseases and their risk factors ...... 47

Benefits and Barriers of a Plant-Based Diet ...... 47 Link Between Diet, Gut Microbiome Diversity and Cardiometabolic Health ...... 48 Short-Chain Fatty Acids ...... 49 Trimethylamine n-oxide (TMAO) ...... 49 Body Weight and Gut Microbiome ...... 49 In Conclusion ...... 51 Key messages ...... 52 Environmental benefits...... 53 References ...... 54

4 GLOBAL HEALTH BURDEN OF CARDIOMETABOLIC DISEASE

5 ardiovascular disease (CVD) continues CARDIOVASCULAR DISEASE to be the leading cause of death Most coronary heart disease manifests when atherosclerotic worldwide, contributing to 31% of all C plaques build up in the blood vessels that supply the heart global deaths.1 In Europe, CVD accounts for (coronary arteries). Plaques narrow the diameter of the blood 45% of all deaths; 49% of deaths among vessel, which can diminish blood flow. In most myocardial women and 40% among men. More than 4 infarctions, an atherosclerotic plaque will rupture, inducing a million people die from CVD across Europe cascade of inflammation and subsequent blood clotting, which every year, with 1.4 million of these deaths acutely blocks blood flow to the heart.6 occurring before the age of 75.2 As previously discussed, CVD is the leading killer in Europe and Important behavioural factors associated with around the world. The good news, however, is that 80% of cardiometabolic disease risk include unhealthy premature heart attacks and strokes are preventable. A , physical inactivity, tobacco use, and diet, regular physical activity, and not using tobacco products excessive alcohol use. Diet can be attributed to are the keys to prevention.7 High blood pressure, dyslipidaemia, about 45.4% of all premature deaths from CVD.3 diabetes, and obesity are physiologic states that increase heart Ischemic heart disease is the leading cause of disease risk. Diets high in saturated and trans fats, and low in death worldwide, with stroke ranked third in fibre, promote atherosclerosis, while high sodium intake mortality causes.4 Despite the relative promotes hypertension. Other behaviour factors, such as availability of blood pressure and cholesterol- tobacco use and sedentary lifestyle, are also risk factors.8 lowering medications, mortality from CVD increased from 2007 to 2017.4 Overall CVD is CVD is an increasingly ubiquitous pathology, no longer reserved estimated to cost the EU economy €210 billion for aging adults. Fatty streaks have been found during autopsies per year. Of the total cost of CVD in the EU, in the aortas of children as young as 10 years old. This same study around 53% (€111 billion) is due to healthcare found streaks in all subjects age 20 and older.9 Other studies costs, 26% (€54 billion) to productivity losses, have demonstrated a high prevalence of atherosclerosis in and 21% (€45 billion) to the informal care of soldier casualties of the Korean War, with an average age of 22.10 people with CVD.5 These findings were corroborated with a later study of autopsied young trauma victims with an average age of 26, Over the last few decades, the importance of noting atherosclerosis in 78.3% of all cases.11 lifestyle factors as leading risk factors for global burden of disease has grown. The top three Despite the high prevalence, CVD is not a natural product of global risk factors are now high blood pressure, aging. As an example, the Tsimané, an indigenous population of excess body weight, and prediabetes or Bolivia, South America, have one of the world’s lowest heart diabetes. Poor nutrition and low consumption disease risk. Researchers at UC Santa Barbara measured of fruits, vegetables, whole grains, legumes, coronary artery calcification (CAC) using CT scans and tested nuts and seeds, as well as low physical activity, blood lipids and inflammatory biomarkers to establish cardiac continue to be the underlying behaviours for risk. All subjects (N=705) were at least 40 years old. increased risk of premature death. Approximately 85% of those tested had no heart disease risk, as determined by CAC and blood tests. 12

6

.In 2016, leading the risk factor forglobal the burden of 1422. -

for increased risk of premature death. death. premature of risk increased for behaviours t, and prediabetes or diabetes. Poor nutrition and low consumption of fruits, vegetables, whole grains, grains, whole vegetables, fruits, of consumption low and nutrition Poor diabetes. or prediabetes and t, Adapted from: Global Burden of Disease Study 2016. Lancet 2017; 390: 1345 390: 2017; Lancet Burden 2016. Disease Study of from: Global Adapted adjusted life year. - ns: DALY, disability

1990. SINCE DISEASES OF BURDEN GLOBAL OF RISK FACTORS 1. LEADING FIGURE Overthe last fewdecades, the importance of lifestyle factors as leading risk factors for global burden of disease has grown weigh body excess pressure, blood high factor: metabolic a was diseases legumes, nuts and seeds, well as low as physical activity, continuebe to the underlying Abbreviatio

7 TYPE 2 DIABETES METABOLIC SYNDROME Other non-communicable diseases, such as type 2 Metabolic Syndrome is a condition characterized by the diabetes (T2D), also pose an immense global health presence of at least three cardiovascular risk factors such burden, ranking 4th in leading causes of disability in 2017. as abdominal obesity, insulin resistance, hypertension, Globally, people with diabetes will spend twice as much and dyslipidaemia (specifically high triglycerides and on healthcare costs per year as non-diabetic persons. LDL and low HDL-C). Metabolic Syndrome increases The same is true for European diabetics4,13, who have a cardiovascular risk and T2D. It impacts 1 in 3 American 2-4 fold increase in risk of death from CVD.14 T2D is on adults21 and 1 in 4 adults in Europe.22 However, it is the rise, with projections of a 48% increase (700 million important to note that metabolic syndrome is not only people) in global incidence by the year 2045. Currently, found in people who are overweight. In one study, 59 million people in Europe (6.3%) have diabetes, with metabolic syndrome was found in ~17% of normal this figure set to grow dramatically. According to the IDF weight individuals.23 atlas 9th edition, this figure will increase to 66 million (7.3%) by 2030 and to 68,1 million (7.8%) by 2045. An NON-ALCOHOLIC FATTY LIVER additional problem is that 1 in 2 people with diabetes do DISEASE not know they have diabetes. Treating diabetes and its Non-alcoholic fatty liver disease (NAFLD) is defined as complications is expensive and takes up between 10% the accumulation of in the liver in people who do not and 18.5% of EU healthcare costs.15 consume excessive amounts of alcohol. NAFLD is closely STROKE associated with obesity, with a prevalence as high as 90% in morbidly obese persons, it is the hepatic Ischemic strokes make up the majority of strokes (85%), manifestation of the metabolic syndrome. NAFLD is with a similar pathology to heart disease. Atherosclerotic expected to become the leading cause of end-stage plaques build up in the blood vessels that supply the liver disease worldwide over the next few decades. In 16 brain, diminishing blood flow. The less common but people with T2D, NAFLD was noted via ultrasound in 70% more dangerous type of stroke is a haemorrhagic stroke. of cases.24 NAFLD is on the rise and can lead to the need Haemorrhagic strokes occur when a blood vessel for liver transplantation.25 The burden of disease related ruptures in the brain, which then disrupts blood flow. to NAFLD is extremely high in the general population, Bleeding from the ruptured vessel is irritating to and the global prevalence of liver steatosis is around surrounding brain tissue and can induce swelling, 25%, including in Europe, but is as high as 46% in the exacerbating tissue damage. Finally, continued bleeding United States. Furthermore, the incidence has gradually from the ruptured vessel can increase pressure inside of increased in the past few decades.26 the brain, further damaging tissues.17 While pathologies differ between ischemic and haemorrhagic strokes, the Fortunately, NAFLD is reversible. As of today, no risk factors are similar. It’s estimated that 90% of stroke pharmacological treatment has been approved for risk comes from modifiable risk factors, including NAFLD. The only recommended treatment of proven smoking, obesity, hyperlipidaemia, hypertension, efficacy is lifestyle modifications, including diet and diabetes, kidney disease, and physical inactivity.18 physical exercise. Projections for global mortality in the year 2040 Personal risks post-stroke continue after hospital anticipate heart disease, stroke, and diabetes to gain an discharge. Of those who survive a stroke, half will suffer even stronger foothold in the top 10 causes of death.4 from chronic disabilities.19 Survivors also double their risk The projected increase in mortality is due in large part to of developing dementia in the future.20 increased urbanization, which was 44.8% of the world in 1994, and is projected to increase to 61.1% by 2025. With increased urbanization comes a diet with increased caloric density and a more sedentary lifestyle pattern.32

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FIGURE 2. BURDEN OF DISEASE BY CAUSE, WORLD, 2017.

Cardiovascular diseases are the leading causes of burden of disease around the world. Total disease burden, measured in DALYs by sub-category of disease or injury. DALYs measure the total burden of disease – both from years of life lost due to premature death and years lived with a disability. One DALY equals one lost year of healthy life. Abbreviations: DALY, disability-adjusted life year; NCD, non-communicable diseases. Adapted from: Roser M, Ritchie H. Burden of Disease. Our World in Data. January 2016. https://ourworldindata.org/burden-of-disease (IHME, global burden of disease). Accessed July 13, 2020.

FIGURE 3. BURDEN OF DISEASE BY CAUSE, WESTERN EUROPE, 2017.

Cancers and cardiovascular diseases are the leading causes of burden of disease in Western Europe. Total disease burden, measured in DALYs by sub-category of disease or injury. DALYs measure the total burden of disease – both from years of life lost due to premature death and years lived with a disability. One DALY equals one lost year of healthy life. Abbreviations: DALY, disability-adjusted life year; NCD, non-communicable diseases. Adapted from: Roser M, Ritchie H. Burden of Disease. Our World in Data. January 2016. https://ourworldindata.org/burden-of-disease (IHME, global burden of disease). Accessed July 13, 2020.

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FIGURE 4. BURDEN OF DISEASE BY RISK FACTOR, WESTERN EUROPE, 2017.

Lifestyle factors are leading risk factors for disease burden. High blood , high blood pressure and excess body weight are in the top four of risk factors in Western Europe and are all linked to increased risk of cardiovascular diseases. Adapted from: Roser M, Ritchie H. Burden of Disease. Our World in Data. January 2016. https://ourworldindata.org/burden-of-disease (IHME, global burden of disease). Accessed July 13, 2020.

10 TYPES OF PLANT-BASED DIETARY PATTERNS

11 lant-based diets have several characteristics that typically followed by people who attempt to minimize may contribute to their role in cardiometabolic animal products in their diets for health, ethical, or P health. These include high fibre content, low environmental reasons.34 Pescatarian diets exclude caloric density, lower saturated fat, beneficial fatty acid animal products but include seafood.35 Lacto-ovo composition (higher in unsaturated fats) and anti- vegetarian diets exclude meat and fish but include inflammatory compounds. There are also beneficial dairy and eggs.36 Vegan diets typically source all effects on gut microbiota, which will be discussed later. calories from plants and exclude all animal products.37 Vegan diets can further diverge into a whole food, There is a spectrum of plant-based eating, varying in the plant-based eating pattern, eliminating foods high in fat, proportion of animal products incorporated into the salt, and sugar from the diet, to confer maximal health diet. Plant-based eating does not automatically exclude benefit. 38 Dietary patterns rich in plant-based foods all animal products but puts plant-based foods at the provide protection against common lifestyle diseases, core. Flexitarian diets include mostly plants, with specifically heart disease, a leading cause of death in occasional intakes of meat, dairy, and eggs. Flexitarian Western populations.39 diets encourage variety rather than restriction and are

FIGURE 5. SPECTRUM OF PLANT- BASED EATING, varying in the proportion of animal products incorporated into the diet. Plant-based eating does not automatically exclude all animal products but puts plant-based foods such as fruits, vegetables, legumes, wholegrains, nuts, seeds, oils and plant-based alternatives to meat and dairy at the core of the diet.

12 HEALTHY AND UNHEALTHY Data was collected from food frequency questionnaires. Researchers assigned positive scores to PLANT-BASED DIET INDEX plant-based foods and negative scores to animal- It is important to note that not all plant-based diets are based foods. A healthful PDI (hPDI) was then created created equal, and that “vegan” doesn’t necessarily to include whole grains, fruits, vegetables, nuts, soy, equate to “healthy.” After all, sugar-sweetened legumes and vegetable oils, as well as an unhealthful beverages (soft drinks) don’t contain animal products, PDI (uPDI), which includes sweetened soft drinks, but their consumption is associated with higher cardio- refined grains, sweets etc. The study showed that diets metabolic risk.40 In addition, the only diet to ever show scoring high on the PDI were associated with lower the reversal of heart disease is a low-fat, whole food coronary heart disease (CHD) risk. Notably, hPDI was plant-based diet.41 Many studies do not differentiate more strongly associated with lower CHD risk, while healthy and unhealthy plant-based diets, but instead, uPDI were associated with an increased risk of CHD.42 lump them all together. For these reasons, researchers This study shows the consequences of over- created a plant-based diet index (PDI) , based on data generalizing food patterns in research: it may downplay that was collected in a series of prospective studies the benefits of diets centred on whole plant-based (Nurses’ Health Study and Nurses’ Health Study II) that foods, while simultaneously providing false reassurance examine how diet, among other factors, impact the of health benefits to those following unhealthy plant- future development of disease. based diets.

FIGURE 6. HEALTHY AND UNHEALTHY PLANT-BASED DIET INDEX AND THE RISK OF CHD.

Diets scoring high on the PDI are associated with lower coronary heart disease risk.

Healthy plant foods include whole grains, , vegetables, soy, legumes, vegetable oils, coffee and tea. The less healthy plant foods include fruit juices, refined grains, fried potatoes, sugar sweetened beverages, sweets and desserts. Animal foods include animal fats, dairy, egg, fish, seafood and meat

Abbreviations: CHD, coronary heart disease; HR, hazard ratio; PDI, plant-based diet index; hPDI, healthful PDI; uPDI, unhealthful PDI. Adapted from: Satija A, et al. J Am Coll Cardiol. 2017;70(4):411-422.

13 PRO-VEGETARIAN FOOD The Portfolio diet is a plant-based diet that focuses on cholesterol-lowering foods.15 To follow the Portfolio PATTERN diet, one should consume about 42 g of nuts, 50 grams There are food patterns in the literature that have of protein from soy or other legumes, and at least 20 established benefits to cardiometabolic health, and grams of viscous, soluble fibre. The 2 gram plant sterol they all emphasize plant-based foods. These dietary recommendation is often achieved through enriched patterns include the Mediterranean diet, Nordic diet, .43. Meta-analysis shows that such a diet Portfolio diet, DASH diet, and vegetarian diet. reduces LDL (commonly referred to as “bad cholesterol”) by ~17%, and 10-year CHD risk by 13%.39 The Mediterranean diet (MedDiet) encourages vegetables, fruits, grains, legumes (incl. soy), nuts, and Vegetarian and vegan diets emphasize the virgin olive oil, with moderate consumption of fish and consumption of vegetables, fruits, soy, legumes, nuts wine. It limits consumption of red and processed meat, and whole grains. Vegetarian diets are void of meats, processed food, and sugar-sweetened beverages.39 A but may include dairy and eggs. Vegan diets exclude recent meta-analysis showed that this diet reduces the all animal-derived products. These dietary patterns risk of both heart disease and the incidence of improves cardiometabolic risk factors and reduce myocardial infarction. There is also an inverse mortality from CHD by 22%.39 association between high adherence to the MedDiet Finally, the DASH diet (Dietary Approaches to Stop and death from heart disease.39 Hypertension) was modelled after vegetarian diets The Nordic diet is a plant-based diet that is traditional in showed beneficial effects on blood pressure. It Nordic countries. It emphasizes the consumption of encourages the consumption of fruits, vegetables, local, seasonal and nutritious foods consisting of whole whole grains, nuts and legumes, and allows for some grains, berries, cabbages, legumes, rapeseed oil, fatty fish, poultry, free/low-fat dairy, and limits saturated fat, fish, shellfish, seaweed, but will restrict the use of cholesterol, red and processed meats, sweets and saturated fat (low-fat dairy) and red and processed sugar-sweetened beverages.44 The DASH diet is also meat. associated with reduced cardiovascular risk and coronary artery disease.39

14 CARDIOMETABOLIC RISK FACTORS

15 BLOOD PRESSURE ypertension, commonly referred to as “high The Coronary Artery Risk Development in Young Adults blood pressure” is a major contributor to study observed ~4,300 young men and women and Hcardiovascular risk. The age- and sex-adjusted their development of cardiac risk factors over 15 years. prevalence of hypertension was 28% in North American Researchers observed lower blood pressure with countries and 44% in European countries at the 140/90 increasing plant-based food consumption. Participants mmHg threshold.45 The European guidelines define consuming the most red and processed meat had 51 hypertension as a blood pressure (BP) ≥140/90 mmHg higher blood pressure. The Omni-Heart study showed (Table 1) while the newest guidelines from the American that those consuming a high protein diet of 25% (half of

Heart Association consider hypertension at BP ≥130/80 which was from plant protein) had a significant mmHg.46 This new threshold gives a hypertension reduction in blood pressure of 7%. The extent of blood diagnosis to nearly half (46%) of all adult Americans.47 In pressure reduction was greater in those suffering from Europe, hypertension affects more than 150 million mild hypertension.52 people, and its prevalence is predicted to rise by 15% Additionally, vegetable consumption is an independent to 20% by 2025.48 factor in blood pressure. The graph below shows that High blood pressure can cause injury to the lining of the blood pressure decreased across quartiles with blood vessels, called the endothelium, which can lay increasing vegetable consumption both for raw and the groundwork for atherosclerosis.49 In addition, cooked vegetables. Those consuming the most consistent high blood pressure stresses the interior vegetables (the 4th quartile) had the lowest blood walls of the heart chambers. The heart then pressure.53 This is relevant because a blood pressure compensates by thickening its walls, which in turn drop of 5 mmHg could reduce overall mortality by 14%, makes the heart pump less efficiently, leading to heart with a 9% reduction in the risk of death from heart failure over time.50 disease.54

The American Heart Association recommends the

DASH diet for the prevention and management of hypertension. Meta-analysis shows a reduction of systolic blood pressure by ~5 points, with the DASH diet.39

FIGURE 7. BLOOD PRESSURE DECREASES ACROSS QUARTILES WITH INCREASING VEGETABLE CONSUMPTION BOTH FOR RAW AND COOKED VEGETABLES.

Adapted from: Chan Q, et al. J Hum Hyper 2014;28(6):353-359.

16 LIPID PROFILE The lipid profile consists of total cholesterol, HDL, LDL, and triglycerides. It is another important predictor of heart disease. Globally, high cholesterol is estimated to be responsible for 2.6 million deaths, with the highest prevalence in high-income countries.55 It even impacts youth, with high cholesterol noted in 7% of children in the United States.56 LDL-C (Low Density Lipoprotein Cholesterol (LDL-C) is typically the target of cholesterol- lowering therapy, as it is a component of the plaques that build up on blood vessel walls, called atherosclerosis, that impede blood flow all over the body.57 The WHO calculated that a 40-year-old man can half his 5-year heart disease risk with a 10% reduction in LDL.55

Plant-rich diets are helpful in both the prevention and treatment of hyperlipidaemia, or high cholesterol. A FIGURE 8. CHANGES IN LDL CHOLESTEROL FROM meta-analysis of diets vs. cardiometabolic risk factors META- ANALYSES OF RANDOMIZED CONTROLLED TRIALS (RCTS ) ON THE EFFECTS OF VEGETARIAN, showed that the Portfolio diet was able to reduce LDL MEDITERRANEAN, PORTFOLIO, NORDIC, AND cholesterol by 17% and that vegetarian and DASH DIET. Mediterranean diets are also associated with beneficial Adapted from: Kahleova H, et al. Nutrients. 2019;11(9):2209. 39 lipid effects. Detailed info for vegan diets is not available.

INFLAMMATION AND ENDOTHELIAL FUNCTION The endothelium refers to the cells lining the insides of cells inhibiting their ability to maintain normal function blood vessels, making direct contact with circulating of the blood vessels.58 White blood cells stick to areas blood. These cells have an important role in the of endothelial dysfunction, and travel to deeper layers prevention and genesis of heart disease. They can be of the blood vessel, initiating an atherosclerotic one of the earliest heart disease indicators before plaque.58 Once in this layer, the white blood cells - structural changes can be detected via angiogram or termed “foam cells” at this point - collect LDL ultrasound. The endothelium is important for heart cholesterol, further increasing inflammation.58 health because it secretes substances that allow the Ingestion of fatty foods may also play a role in blood vessels to constrict, dilate, and form clots as endothelial health. One study was able to show needed.49 endothelial dysfunction in healthy people after a single Several risk factors influence endothelial health, one of high-fat .59 Factors associated with endothelial which is hypertension. Shear stress from increased injury include elevated LDL-C, high blood glucose, pressure inside of blood vessels can injure endothelial diabetes, and high blood pressure.60

17 Inflammation, commonly measured as C-Reactive OBESITY/OVERWEIGHT/ Protein (CRP), is the preceding factor to all steps of plaque formation.61 Chronic, low levels of inflammation ADIPOSITY can yield ominous predictions of future cardiovascular Globally, the prevalence of overweight and obesity has events. In the Women’s Health Study, a cohort of over tripled since 1975 and was at 39% in 2016. The trend 28,000 women had baseline high-sensitivity CRP levels continues in children, with a 4% prevalence in 1975, and drawn and were monitored for the occurrence of an overall 18% prevalence in 2016.67 These trends have cardiac events over the course of ~8 years. Women dire health consequences, increasing the risk of all with the lowest CRP levels at baseline were the most cardiometabolic risk factors.68 Excess body fat is not just likely to be event-free. Participants with the highest CRP dormant energy storage, but rather an endocrine at baseline had a 4.4 times higher risk for cardiac organ. Adipose tissue releases hormones responsible events.62 for appetite regulation, insulin sensitivity, and inflammation.69 Excess fat stores can lead to low-grade Plant-based diets are associated with lower CRP levels inflammation, proposed to be caused by a lack of when adhered to for at least two years, according to vasculature in adipose tissue stores.70 one review and meta-analysis of 18 studies.63 In contrast, intake is associated with higher CRP Perhaps a more important risk factor than body mass levels.64 Additionally, endothelial health can be index (BMI) is waist to height ratio. Ratios greater than maintained and even improved with a plant-based diet. 0.5 represent increased proportions of visceral fat. For An inverse relationship exists between consumption of example, a man tall at 183 cm should have a waist no saturated fat (found primarily in animal foods and some larger than 91 cm. Storing fat around the abdomen tropical oils) and flow-mediated dilation (a method of poses increased cardiovascular mortality, even in testing endothelial health).65 individuals with a normal BMI.71 Whole- intake is associated with less visceral adipose tissue, as

demonstrated in a subset study of the Framingham Heart Study. Researchers noted that visceral adipose tissue volume was ~10% lower in individuals eating at least 3 servings of whole grains per day, compared with individuals who consumed almost no whole grains.72 Additionally, researchers Y. Yang and MA Beydoun found the highest BMIs and waist circumferences in participants consuming meats in the highest quintiles, and the lowest BMIs and waist circumferences in participants with meat consumption in the lowest quintiles.73

FIGURE 9. WOMEN WITH HIGHEST CRP AT BASELINE HAD 4.4 TIMES HIGHER RISK FOR

CARDIAC EVENTS THAN WOMEN WITH THE LOWEST CRP LEVELS AT BASELINE.

Abbreviations: hsCRP, high-sensitivity C-Reactive Protein. Adapted from: Ridker Paul M. Circulation. 2003;107(3):363-369. 66

18 Plant-based diets have shown to be an effective tool in months.74 A meta-analysis also confirmed that weight control. In the BROAD study, researchers vegetarian diets help with weight loss, delineating that demonstrated impressive weight loss results with a a vegan diet conferred the most weight loss.75 low-fat plant-based (7-15 En% from fat) diet, instructing Additionally, data from the Adventist Health Study II their participants to eat to satiation and not count shows that those following a vegan diet are the only calories. This diet was able to lower BMI by 4.4 points, subset of people who average a healthy BMI and that and participants maintained that weight loss at 12 BMI increases as more animal products enter the diet.76

FIGURE 10. BMI AND DIETARY PATTERNS.

Adapted from: Tonstad S et al. Diabetes Care. 2009;32(5):791-796.

GLUCOSE METABOLISM The incidence of T2D, marked by impaired glucose glucose uptake by muscles, and additionally with the metabolism, is lowest in vegans and highest in conversion of glucose into glycogen stores.78 Since .76 Plant-based diets are thought to improve glucose cannot enter cells, it’s left in circulation, glucose metabolism through several mechanisms via promoting more insulin secretion by pancreatic beta- reduction of insulin resistance in body tissues and by cells. Persistent overworking of pancreatic beta-cells improvement in the function of pancreatic beta cells, can lead to dysfunction and beta-cell death, further which are responsible for secreting insulin that allows perpetuating hyperglycemia.78 One study glucose to enter cells.77 demonstrated greater lipid accumulation with a higher fat (39%) diet, and less accumulation with a lower fat Greater stores of fats within muscle cells, are associated (31%) diet.79 with greater insulin resistance as fat interferes with

19 Beyond the target tissues, dietary saturated fats also impact the beta-cells in pancreas that secrete insulin. The European Association of the study of Diabetes Saturated fatty acids, found mostly in animal products (EASD) recognizes diet as an important contributor in a and some tropical oils, can reduce beta-cell cost-effective, multi-disciplinary approach to the proliferation, and even induce beta-cell death. management and treatment of diabetes, encourages Conversely, unsaturated fatty acids, found in non- the consumption of whole grains and adequate fibre 80 animal foods, show protective effects. and additionally recommends reducing saturated fat A 16-week randomized controlled trial (RCT) intake in favour of polyunsaturated fats. demonstrated that a low-fat, plant-based diet was able The American Diabetes Association recognizes to improve insulin sensitivity and beta cell function in beneficial effects for diabetics following 77 participants without diabetes. Furthermore, a meta- Mediterranean, vegetarian, and DASH diets, and analysis confirmed improved glucose control with additionally recommends reducing saturated fat intake 39 DASH, Mediterranean, and vegetarian diets. in favour of polyunsaturated fats.81

NON-ALCOHOLIC FATTY LIVER DISEASE Non-alcoholic fatty liver disease (NAFLD) is defined as the accumulation of fat in the liver in people who do not consume excessive amounts of alcohol.

Plant-based diets have been shown to be particularly effective for NAFLD: vegetarian diets are associated with a 21% lower risk of NAFLD compared with non- vegetarian diets, even after adjustment for BMI. On the other hand, replacing a serving of soy with a serving of meat or fish was associated with 12%-13% increased risk.27 In an RCT including 60 overweight or obese adults with NAFLD, an 8-week DASH diet reduced body weight and improved liver enzymes and markers of insulin resistance.28 A few studies have also

demonstrated that the MedDiet may be used as an FIGURE 11. CHANGES IN HBA1C (MARKER OF effective diet for NAFLD.29 While weight loss may be LONG-TERM GLUCOSE CONTROL) IN META- ANALYSES OF STUDIES USING MEDITERRANEAN, one of the mechanisms behind improvements in DASH, AND VEGETARIAN DIETS. NAFLD,30 plant-based diets low in saturated fat, high in

Abbreviations: HbA1c, glycosylated haemoglobin A1c. fibre and unsaturated fatty acids, may have a positive Adapted from: Kahleova H et al. Nutrients. 2019;11(9):2209. impact on NAFLD even in the absence of weight loss.31

20 PLANT COMPONENTS AND FOOD GROUPS

21 NUTS rom a botanical point of view, nuts are defined as dried fruits with one (exceptionally two) unattached or free seed within a hard shell. However, the term “nut” is also popularly applied to any hard-walled, edible, oily seed. In any Fcase, nuts are considered a high energy density food because of their high fatty acid (mainly unsaturated fatty acids) content. They are relatively low in carbohydrates. Moreover, nuts are rich in fibre, minerals, and other bioactive compounds such as polyphenols.82,83 Given this exceptional nutritional profile, well-known beneficial properties against several chronic diseases have been attributed to nuts.

FIGURE 12. NUTRIENT COMPOSITION OF DIFFERENT TYPES OF NUTS.

Source: U.S. Department of Agriculture (USDA) National Nutrient Database for Standard Reference. https://fdc.nal.usda.gov/index.html. Accessed July 13, 2020

The bold green numbers indicate the highest values.

All the nuts are unsalted; , brazil nuts, hazelnuts, pecans and walnuts are unroasted; , macadamia nuts and pistachios are dry roasted.

22 Nut consumption has shown to have beneficial effects a lower risk of T2D in women. Those with the highest on the cardiovascular system. In large epidemiologic nut consumption (28 g/day; ≥5 days a week) had a 27% studies, the frequency of nut consumption was lower risk of developing T2D (RR= 0.73; 95CI: 0.60–0.89) consistently related to lower rates of CHD, incidence than those who never or almost never consumed and mortality from CVD, and total death. 84 Additionally, nuts.90b in a few studies, the frequency of nut consumption was These results are in line with those from the PREDIMED inversely related to sudden death,85 peripheral artery study (N=7,210 subjects), where the upper category of disease,86 and arrhythmia.87 nut consumption (>3 servings/wk) had a lower One of the landmark studies in this area is the prevalence of T2D than the lower category (<1 PREvención con DIeta MEDiterránea (PREDIMED) serving/wk of nuts): OR=0.87 (0.78 to 0.99; P- study, a multicentre, parallel-group clinical trial trend=0.043).91 evaluating the effect of the MedDiet on the primary Nuts may protect from CVD through different prevention of CVDs in more than 7,000 participants at mechanisms including their recognized lipid-lowering high risk of CVD. The main results of this RCT effect,92 and other potential mechanisms such as demonstrated that a MedDiet enriched with a mix of improving the function of vessels,93 reducing nuts (15g/day of walnuts, 7.5g/day of almonds and postprandial glycaemia and insulin resistance when 7.5g/day of hazelnuts) reduced the risk of CVD by substituting carbohydrates94 or changing gut 30%88, and the risk of peripheral artery disease by 52%89. microbiota composition and function (see later).95 In a 2017 meta-analysis,90 researchers analysed the It is important to mention that although nuts are energy- associations between the intake of total and specific dense food, epidemiologic studies have demonstrated types of nuts with the risk of CVD in three large an inverse association between nut intake and risk of prospective cohort studies. The paper included weight gain, obesity,96 and metabolic syndrome.96,97 5,063,439 person-years of follow-up: 76,364 women Additionally, in clinical trials, there was no effect on from the Nurses’ Health Study, 92,946 women from the adiposity in individuals who supplemented with nuts.98 Nurses’ Health Study II, and 41,526 men from the Health The PREDIMED-Study, a MedDiet supplemented with Professionals Follow-up Study. Higher consumption of nuts showed a higher reversion of metabolic syndrome total and specific types of nuts was inversely than a low-fat diet.99 associated with the risk of total CVD and CHD. Compared to the reference category, who reported to A recent meta-analysis (6 cohort studies of 420,890 consume nuts ‘never’ or ‘almost never’, those who subjects and 62 RCTs with 7,184 participants) consumed one serving of nuts (28 g) five or more times demonstrated that nut intake may be associated with per week had pooled multivariable hazard ratios for decreased risks of metabolic syndrome and CVD and CHD 0.86 [95% CI 0.79–0.93, P trend 0.0002] overweight/obesity and lower body weight measures. and 0.80 [95% CI, 0.72–0.89, P trend <0.001], respectively. Consumption of peanuts and tree nuts The meta-analysis of prospective cohort studies (two or more times/week) and walnuts (one or more (N=420,890 subjects) showed that for every 1e times/week), was associated with a 13%-19% lower risk serving/week increase in nut consumption, the risk of metabolic syndrome was reduced by 4%, by 3% for of total CVD and 15–23% lower risk of CHD. overweight/obesity. However, a 5% non-significant In the Nurses’ Health Study (N= 83,818 female subjects), reduction in the risk of obesity was shown96. the intake of different types of nuts was associated with

23

FIGURE 13. NUT CONSUMPTION AND RISK OF METABOLIC SYNDROME AND OVERWEIGHT/OBESITY: RESULTS FROM META-ANALYSIS (N=420,890 SUBJECTS).

For every one serving/week increase in nut consumption, the risk of metabolic syndrome was reduced by 4%, by 3% for overweight/obesity. A 5% non-significant reduction in the risk of obesity was shown.

Abbreviations: CI, confidence interval. Adapted from: Li H, et al. Nutrition and Metabolism. 2018;15(1):1-10.

In summary, nuts, due to their nutritional profile, possess a wide range of benefits on CVD and modulate related risk factors, such as lipid metabolism, oxidative stress, and inflammation,100 without affecting body weight.

SOY ( max) belong to the family of the is highly digestible.102 A contains ± 20% oil from Leguminosae but have a unique macronutrient which approximately 12-15% comes from saturated fat, composition when compared to other legumes. They 23-29% from oleic acid (18:1n-9; MUFA); 53-55% from are especially high in protein and oil (predominantly linoleic acid (18:2n-6, LA), and 6-8% from α-linolenic acid unsaturated fat), whereas other legumes are almost fat- (18:3n-3, ALA). It is a source of vitamins B6, E, K, and free and contain mostly starch. Soybeans are low in folate, and the minerals calcium, iron, magnesium, carbohydrates and contain about 6 grams of fibre (per copper, potassium, and . The amounts of 100g).101 is a high-quality protein, meaning it these nutrients vary among different soy foods contains all of the essential amino acids in sufficient according to how the soy foods are produced.103 quantities to help meet the body’s requirements and it

24

FIGURE 14. NUTRIENT COMPOSITION OF SOY- BASED ALTERNATIVE TO YOGURT AND SOYDRINK.

Alpro – website nutrition information. www.alpro.com

Soy foods have been in the human diet for a long time, It was not until the 1970s that the medical community and they have served their consumers well. This is became aware of the value of soy in lowering serum typically so in the Orient where soy has been cholesterol.107 This new interest in soy was triggered by consumed for over 2000 years. Of particular interest is the work of Cesare Sirtori1 who demonstrated Japan, one of the countries with the largest soy spectacular reductions in serum lipids in consumption.104 During the time of greatest soy hypercholesterolemic patients who replaced the meat consumption, Japan also had one of the longest in their diets with soy.108 longevity records on the face of the planet.105,106 This fact By 1995 there were enough studies on soy and its effect must be seen as a testament, in part, to the health on blood lipids for Anderson et al. to publish the first benefits of soy in the Japanese diet. meta-analysis. He demonstrated that the replacement

1 Sirtori C: Member of scientific advisory board Alpro Foundation

25 of animal protein in the diet with soy protein was An advantage of incorporating soy foods in the diet is associated with a significant reduction in total that, as discussed above, they potentially reduce LDL-C cholesterol and LDL-C.109 The initial total cholesterol through both direct and indirect mechanisms: level of the subjects influenced the cholesterol- • Direct effect: Soy protein directly lowers LDL- lowering effect. This meant that the greater the initial C by approximately 3 to 5%. One theory to total cholesterol level, the larger the reduction in total explain this effect is that peptides formed cholesterol and LDL-C. In subjects with initially severe from the digestion of soy protein upregulate hypercholesterolaemia (total cholesterol above 335 LDL-C receptors in the liver, allowing mg/dL or 8.7 mmol/L), a decrease of 19.6% in total cholesterol to be removed from the cholesterol and 24% in LDL-C was observed. Shortly bloodstream more efficiently.120 after this publication, in 1999, the US Food and Drug • Indirect or food displacement effect: When Administration (FDA) brought out a health claim for soy soy foods replace common sources of animal- stating that “daily consumption of 25 grams of soy based protein in Western diets, which are protein, as part of a diet low in saturated fat and often high in saturated fat, the favourable cholesterol, may reduce the risk of heart disease”.110 change in fatty acid intake will lower LDL-C.119 Since the FDA claim was approved, more than 10 In line with the validation of scientific countries2 have adopted similar claims including evidence, the European Food Safety Authority Canada in 2015.116 Subsequent meta-analyses (EFSA) approved the following claims demonstrated consistent LDL-C lowering effects of soy concerning replacing foods high in saturated in the range of 3 to 5%.112–114 Although the lipid-lowering fats: Replacing saturated fat with unsaturated effects of soy protein are much more modest than fat in the diet maintains normal blood initially reported by Anderson et al. (6), they are still cholesterol levels.120b relevant at the clinical and population levels as for every

1% reduction in LDL-C there is a corresponding 1%–2% 115 reduction in cardiovascular events. Soy, as part of a healthy diet, has shown clinical utility in reducing serum cholesterol.121–125 Reductions in serum The FDA is currently reviewing the data and might cholesterol from a dietary portfolio including soy replace it with a qualified health claim, which requires a (together with nuts, fibre, whole grains (e.g. and lower scientific standard of evidence than a health barley), and plant sterols in the form of ), claim but would still confirm a beneficial effect. A recent taken under closely supervised conditions with all food new meta-analysis confirmed that daily consumption of provided, were in the range of 25 to 30% .126 While each 25g of soy protein does result in a modest, but of these foods contributed a small amount to the LDL-C significant, reduction in total and LDL-C – beyond the reduction, the results from all of these foods eaten effect seen from lowering saturated fat intake.118 together were even more impressive.127 Indeed, soy also provides another advantage in that it Beyond the effects on lipids, soy protein can also lower displaces foods that are higher in saturated fat such as blood pressure. A meta-analysis by Barnard et al. animal-based products and which raise serum demonstrated that vegetable proteins (including soy) cholesterol.119 An analysis by Kris-Etherton et al. showed lowered blood pressure, another risk factor for heart quite nicely the displacement effect that soy had on disease.128 Several other meta-analyses have shown that LDL-C, in addition to the direct effect that soy likely systolic and diastolic blood pressure is reduced by reduces LDL-C production by the liver.119 approximately 2.5 and 1.5 mmHg, respectively, upon

2 Including Japan, South Africa, the Philippines, South Korea, Turkey, Malaysia, India, Brazil, Chile, Columbia, Ecuador and Peru.

26 soy consumption.129–132 The mechanism by which soy cancer.134–137 However, more recent data has shown that protein exerts its blood pressure lowering effects has in humans soy consumption has been associated with not been identified but may be related to bioactive a reduced, not an increased, risk of breast cancer and peptides or vasodilation by isoflavones present in soy. possibly also with a lower risk of prostate cancer.138–142 The public health benefits of even the modest Concerns have also been expressed about the use of proposed blood pressure lowering effects of soy genetically modified soy and the effect that soy protein are relevant as reducing systolic blood pressure production might have on the environment.143 These by just 2–5 mmHg may reduce stroke and CHD by 6%– are important and consumers should use sustainably 14% and 5%–9%, respectively.133 produced soy.144,145 The above-mentioned concerns should not discourage the public from consuming soy There have been a number of concerns raised about for cardiovascular health. soy consumption, foremost of which has been the fact that soy was thought to increase the risk of breast

In conclusion, since the FDA first allowed a health claim, soy has been shown to have a significant and consistent effect in lowering LDL-C in the 3 to 5% range and in lowering systolic and diastolic blood pressure by approximately 2.5 and 1.5 mmHg. It is, therefore, a valuable and versatile food that contributes high quality protein and a beneficial fat composition (high in unsaturated fats, low in saturated fats) to the plant-based diet, while at the same time reducing important risk factors for CVD.

LEGUMES Legumes are the fruit or seed of plants from the family Legumes are a good source of fibre, and Fabaceae or Leguminosae, including alfalfa, broad carbohydrates, and are considered a low-glycaemic- beans, clover, lupine, soybeans, peanuts, green/dry index food. This means glycemia increases gradually, beans and peas, chickpeas, and lentils.146 “Pulses” is without spiking, as legumes are broken down slowly another term that is widely used to refer to legumes, after consumption. Legumes are also rich in some although according to the FAO, it only refers to vitamins, minerals (including magnesium and leguminous crops that are harvested simply for dry potassium) and polyphenols.148 It is noteworthy that grain.147 soybeans differ from the rest of the legumes in terms of quantity and quality of protein and poly-unsaturated fat content.149

27

FIGURE 15. NUTRIENT COMPOSITION OF BOILED SOYBEANS AND SELECTION OF LEGUMES.

Abbreviations: ND, not detectable; Adapted from: Messina M, Nutrients. 2016;8(12):754. Source: U.S. Department of Agriculture (USDA) National Nutrient Database for Standard Reference. https://fdc.nal.usda.gov/index.html. Accessed July 13, 2020

The bold green numbers indicate the highest values.

The nutritional profile of legumes endows them with a contrast, there was no association between wide range of potentially beneficial cardiometabolic consumption and CVD mortality, myocardial infarction, health properties. Their consumption, within a balanced stroke, or diabetes. It is important to note that these plant-based diet, is therefore recommended by studies did not distinguish between non-soy and soy multiple international health organizations.150–152 legumes, although these have a different nutritional profile. Becerra-Tomás and coworkers153 are the only Results from the latest systematic reviews and meta- ones that have differentiated these types of legumes analyses of prospective cohort studies,153,154 which when examining the association with diabetes. They provide us with the highest level of scientific evidence, reported that non-soy legume consumption was show that legumes are associated with a significant associated with a 15% lower risk of diabetes. decrease in the risk of CVD, CHD and hypertension. In

28 To date, only one cohort study has evaluated the which revealed that consuming 132g per day of pulses association between legume consumption and obesity reduced body weight by 340g compared to diets development, showing a 15% lower risk.155 These without pulse intervention.156 findings mirror those from a meta-analysis of 21 RCTs,

Legumes may protect against cardiometabolic diseases by modulating different risk factors involved in their pathogenesis, such as glucose and lipid metabolism, high blood pressure, and adiposity. These benefits cannot exclusively be attributed to one of the nutritional components, but rather to the synergy between all of them.

It is important to highlight that legumes can contribute to environmental sustainability as reported in the 2019 EAT- Lancet commission report on healthy diets from sustainable food systems.157

WHOLE GRAINS AND FIBER to the source of the . Sources of whole grains that contain the viscous soluble fibre beta- Whole grains are variably defined. The American glucan, such as oats and barley and their isolated fibres Association of Chemists (AACC), defines whole (for which there are FDA,162,163Health Canada,164,165 and grains as the intact, ground, cracked, or flaked EFSA166 approved health claims for cholesterol caryopsis, whose principal anatomical components— reduction), show evidence of benefit. Other sources of the starchy endosperm, germ and bran —are present in whole grains, such as wheat, rye, and rice, do not show the same relative proportions as they exist in the intact evidence of benefit.161,167,168 Studies consistently show caryopsis.158,159 This definition was adopted by various similar results for the effect of whole grains on regulatory bodies, including EFSA.160 Sources of whole glycaemic control. Whereas whole grains from barley grains include both the cereal grains (e.g. wheat, rice, and barley beta-glucan have shown improvements in oats, barley, corn, wild rice, and rye) and pseudo-cereal fasting glucose in people with and without grains (e.g. , amaranth, and buckwheat), but not diabetes,169,170 and whole grains from oats and beta- oil seeds (e.g. soy, flax, sesame seeds, and poppy glucan have shown improvements in HbA1c and fasting seeds). blood glucose in people with T2D,170,171 these advantages have not been seen for whole grain Systematic reviews and meta-analyses of RCTs have sources from whole wheat or wheat bran when used shown that whole grain interventions improve lipids, as either test or control treatments.172-174 Other important including triglycerides and the established therapeutic physiological benefits such as contribution to stool target LDL-C, in people with and without diabetes over bulking and laxation, have been observed in RCTs for 2-16 weeks of follow-up.161 Any lipid-lowering whole wheat and wheat bran.175 advantages, however, appear to be entirely attributable

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FIGURE 16. NUTRIENT COMPOSITION OF SELECTION OF WHOLE GRAINS.

Source: U.S. Department of Agriculture (USDA) National Nutrient Database for Standard Reference. https://fdc.nal.usda.gov/index.html. Accessed July 13, 2020

These distinctions between sources of whole grains are Other lines of evidence from dietary pattern data not apparent in the epidemiology. Systematic reviews suggest benefits of whole grains irrespective of source. and meta-analyses of prospective cohort studies have The PREvencion con DIeta MEDiterranea (PREDIMED) shown a protective association of total whole grains study, a large Spanish multicentre randomized trial, (where wheat is the dominant source) and total cereal showed that compared to a low-fat control diet, a fibre (as a proxy of whole grains) with incidence of CHD whole-grain containing MedDiet supplemented with in people with and without diabetes.176, 177 It does not either mixed nuts or extra-virgin olive oil reduced major appear that these benefits are entirely explained by CV events by ~30%,88 diabetes incidence by 53% whole grain sources high in viscous soluble fibres, such (single-centre finding),178,179 and increased reversion of as oats and barley, as total soluble and insoluble fibres metabolic syndrome by ~30% 99 over a median follow- (most of which derive from whole grain sources) show up of 4.8 years in 7,447 participants at high CV risk. similar associations with incidence of CHD in pooled Studies of intermediate cardiometabolic risk factors analyses.177 have also shown that whole grain containing diet, such as the Mediterranean, Portfolio, DASH, Nordic, and

30 vegetarian diet improve glycaemic control, blood prospective cohort studies that show that adherence to pressure, or lipids without an emphasis on one type of diets containing whole grains is associated with whole grains over another.39,126,180,181 This evidence aligns reduced incidence of diabetes and CVD.39,182,183 with systematic reviews and meta-analyses of

The evidence supports higher intake of whole grains (especially the viscous fibre-containing whole grains from oats and barley). More research is needed to understand the role of specific sources of whole grains in cardiometabolic disease prevention.

FRUITS AND VEGETABLES alone (>3 servings/day), or vegetables alone (>4 servings/day) are associated with a reduction in International dietary guidelines and clinical practice diabetes incidence,194 CHD incidence and mortality,195 guidelines for diabetes and heart health are universal in stroke incidence and mortality,195 CVD incidence and their recommendation to consume fruits and mortality,195 and all-cause mortality.196 vegetables.184–188 In addition to providing essential vitamins and minerals and important bioactives,189 fruits Diets containing fruits and vegetables further support and vegetables have shown many cardiometabolic their cardiometabolic benefits. Mediterranean, advantages. Studies have shown that diets Portfolio, DASH, Nordic, and vegetarian diets including supplemented with fruit (fresh or freeze-dried) improve high fruit and vegetable intake have shown HbA1c in individuals with and without T2D over 6 to 20 improvements in intermediate cardiometabolic risk weeks.190 Fruit has also been show to decrease the factors such as glycaemic control, blood pressure, and established lipid target for CVD prevention, LDL- lipids in the RCTs,126,197,180,181 and an association with cholesterol, and blood pressure191 over 2 weeks to 6 reductions in the incidence of diabetes and CVD in the months. Supplementation with both fruits and prospective cohort studies.39,182,183 vegetables (provided as either foods or supplements) With the growing public health concern about the has been shown to improve diastolic blood pressure contribution of to the epidemics of obesity and over 6 weeks to 6 months in individuals with metabolic diabetes, there is a worry that not all sources of fruits syndrome.192 These improvements in cardiometabolic and vegetables share the same cardiometabolic risk factors have been extended to harder surrogate benefits. There is a particular concern that fruit, more endpoints of atherosclerotic CVD (ASCVD). RCT results than vegetables, may contribute to excess intake of show that increased intake of fruit and vegetables leads sugars and so fail to achieve the intended benefits.198– to improvement in diastolic blood pressure and a 200 Public health policies have reflected this concern clinically meaningful regression in carotid intima medial emphasizing vegetables before fruit intake and thickness, as a direct marker of atherosclerosis, in discouraging the intake of certain sources of fruit, such people with type 1 and T2D over one year.193 as 100% fruit juice and .185,201,202 However, The The evidence for improvements in intermediate effect of fruit (up to 3 servings a day) on decreasing cardiometabolic risk factors is reflected in the intermediate cardiometabolic risk factors in RCTs190–193 epidemiology on important clinical outcomes. Higher and the protective association with diabetes and intakes of fruits and vegetables (>5 servings/day), fruit cardiovascular outcomes in prospective cohort studies

31 is equal to or even greater than that from vegetables.195 diets, provide additional evidence of benefit for 100% fruit juice and dried fruit have also shown diabetes and CVD in RCTs and prospective cohort improvements in aspects of glycaemic control in studies.88,180,197 The relative advantage of different fruits isocaloric substitution of starch in RCTs,190,203–205 and in a diet, however, may depend on the type, source, been associated with reduced risk of metabolic and/or preparation. A re-analysis of an RCT of a 6- syndrome206 and hypertension207 at moderate levels of month low-GI intervention in people with T2D showed intake (≤150-200mL/day) in non-linear dose-response that the reduction in A1c was explained by the low-GI analyses in prospective cohort studies. Diets that temperate climate fruit (apples, pears, berries, etc.) as explicitly include 100% fruit juice and dried fruit as opposed to the other aspects of the low-GI sources of fruit, such as the Mediterranean and DASH intervention.208

Higher intake of total fruits and vegetables (at least 400g per day) remains a cornerstone of heart-healthy diets. Mediterranean, Portfolio, DASH, Nordic, and vegetarian diets including at least 5 portions of fruit and vegetables a day have shown improvements in intermediate cardiometabolic risk factors and an association with reductions in the incidence of diabetes and CVD.

32 DIFFERENT PLANT-BASED FOOD PATTERNS

33 PORTFOLIO DIET he Portfolio diet is a plant-based diet that was first developed in the early 2000s as a “portfolio” of T cholesterol-lowering foods, each of which has a EFSA, FDA or Health Canada approved health claim for the reduction of cholesterol.164-166,209-212 The original diet was built on a foundation of a low-saturated fat NCEP (National Cholesterol Education Program) Step II diet

(≤7% saturated fat and ≤ 200 mg dietary cholesterol) with the addition of four cholesterol-lowering foods or pillars (based on a 2000 kcal diet): 45 g nuts (tree nuts or peanuts); 50 g plant protein (soy products or dietary pulses, such as beans, peas, chickpeas, and lentils); 20 g viscous soluble fibre (oats, barley, psyllium, eggplant, okra, apples, oranges, or berries); and 2 g plant sterols (plant sterol-enriched margarine or supplements).121-125 The Portfolio diet has since been expanded and enhanced to include “heart-healthy” monounsaturated fats (MUFA) (extra virgin olive oil, cold-pressed canola/soybean oils, or avocados) as the 5th pillar in replacement of high glycaemic index carbohydrate FIGURE 17. EFFECT OF THE PORTFOLIO DIET (13% replacement providing 26% energy from MUFA).213 VERSUS FIRST- LINE THERAPY WITH A STATIN (20mg LOVASTATIN) ON LDL CHOLESTEROL IN 46 PORTFOLIO DIET AND CARDIOMETABOLIC PARTICIPANTS WITH HYPERLIPIDEMIA. RISK FACTORS Adapted from: Jenkins DJA, et al. JAMA. 2003;290(4):502-510. The biological basis for the intended cardiovascular risk reduction with the Portfolio diet is the “LDL-C There is compelling evidence from RCTs that the hypothesis”. There is now an established international Portfolio diet produces clinically meaningful reductions consensus214-216 that LDL-C is causal in the pathogenesis in LDL-C. The main clinical question tested in the early of atherosclerotic CVD (ASCVD). The consensus is trials of the Portfolio diet was whether the small based on multiple lines of high-quality evidence from individual LDL-C effects of the cholesterol-lowering cardiovascular outcomes trials (through the Cholesterol foods included in the pattern were additive. Updated Treatment Trialists Collaboration [CTTC]) involving over studies continue to show that each component can 200,000 patients randomized to three different classes lower LDL-C by 5-10%.92,118,167,220-229 It was unclear of drugs [statins, ezetimibe, PCSK9 inhibitors],217 whether these effects could be combined or summed Mendelian randomization studies of gain and loss of in a single diet to produce a meaningful “drug-like” function mutations in the targets of these drugs that reduction in LDL-C. A series of RCTs were undertaken to modify exposure to LDL-C (LDLR, HMGCR, NPC1L1, address this question in which all foods were provided PCSK9),218 and prospective cohort studies of the under metabolically controlled feeding conditions in absolute magnitude of exposure to plasma LDL-C and people with hyperlipidemia.121,125,122,124,123 These trials the risk of ASCVD.219 proved the efficacy of the Portfolio diet, showing the predicted ~30% reductions in LDL-C.121-125 A “head-to- head” trial with first-line drug therapy further showed that the in-trial reductions achieved were similar to

34 those seen with 20mg lovastatin (-28.6% versus - ASCVD risk.43 The pooled analysis of seven trial 30.9%).122 A subsequent large multicentre RCT of comparisons in 439 participants with hyperlipidaemia effectiveness tested whether the reductions in LDL-C showed that the Portfolio diet lowered the primary were durable under real-world conditions over the outcome, LDL-C, by 17% (21% in efficacy and 12% in longer-term, in which the Portfolio diet was effectiveness trials) compared to the NCEP Step II diet administered as routine or intensive dietary advice alone with high certainty evidence. (without provision of foods) over 6-months in people Calculations showed that the intended combination with hyperlipemia.213 Although the reductions in LDL-C with an NCEP Step II diet could be expected to produce of 10-15% were smaller, this trial provided an important LDL-C reductions of ~29% (33% in efficacy and 15% in proof of concept, as the reductions were proportional effectiveness trials) in clinical practice, reductions which to the adherence to the diet (the average adherence would exceed the lower limit of efficacy of first-line among participants was 43% to the original four therapy with statins (20%) and the upper limit of efficacy components in the intensive arm) and remained of second-line therapy with ezetimibe (22%).236 Beyond clinically meaningful despite the lower adherence in LDL-C, improvements in other atherogenic aspects of both arms.213 the lipid profile were also seen with moderate to high The strength of these findings was recently confirmed certainty evidence (-14% non-HDL-C, -15% apoB, -16% in a study by the Diabetes and Nutrition Study Group triglycerides), blood pressure (-1.75 mmHg), and (DNSG) of the European Association for the Study of inflammation (-32% CRP) culminating in a reduction in Diabetes (EASD) that looked at available RCTs and used estimated 10-year CHD risk by the Framingham Risk the GRADE system to quantify and assess the certainty Score of ~13% (20% in efficacy and 9% in effectiveness of the evidence for the effect of the Portfolio diet on trials).

35

FIGURE 18. PORTFOLIO DIET.

Source: Jenkins D, et al. The Portfolio Diet, An evidence-based eating plan for lower cholesterol infographic.

36 density density - e presentede on the cholesterol, high -

MD. Adapted from:Chiavaroli L, et al. Prog CardiovascDis. cholesterol was provided so that it could b - reactive protein; DBP, diastolic blood pressure; HDL - density lipoprotein cholesterol; SBP, systolic blood pressure; SMD, standardized mean - high - HDL, non - C AND VARIOUS CARDIOMETABOLIC RISK FACTORS. FACTORS. RISK CARDIOMETABOLIC VARIOUS C AND -

s in 439 participants. participants. 439 in s RCT C, total cholesterol. *The reciprocal of the actual pooled MD (0.01 [−0.03,0.05]) for (0.01 *Thereciprocal of [−0.03,0.05]) C, total MD HDL pooled the actual cholesterol. - density lipoprotein cholesterol; MD,mean difference; non - analyses of seven seven of analyses , apolipoprotein B; CHD, coronary heart disease;CI, confidence interval; CRP, C - C, low

- 53. . POOLED. EFFECT OF THE PORTFOLIO DIET ON LDL - 9

FIGURE 1 metaData on based Abbreviations: ApoB lipoprotein; LDL difference; TG, triglycerides; Total samescale (benefitvs. harm) as other the endpoints. ** %was change calculated by dividingthe median baseline level the by 2018;61(1):43

37 Evidence collected in RCTs and subsequent systematic clinical CV events. We await the results of the reviews and meta-analyses has caused the benefits of Combined Portfolio Diet and Exercise Study (PortfolioEx the Portfolio diet to be recognized in many international trial), a 3-year multicentre RCT on the effect of the guidelines, including the clinical practice guidelines of Portfolio Diet plus exercise on carotid plaque burden the Canadian Cardiovascular Society (CCS),231 Diabetes assessed by vascular magnetic resonance imaging Canada,232 Heart UK,233 Heart Foundation of Australia,234 (MRI) in high CV risk people, 50% of whom have the American College of Cardiology /American Heart diabetes (ClinicalTrials.gov Identifier, NCT02481466). Association,235 and the European Atherosclerosis

Society (EAS)236. At the same time, each of the food components have been recognized for their LDL-C MEDITERRANEAN DIET lowering by the joint task force of the European Society of Cardiology (ESC) and EAS.237 The MedDiet is the traditional diet of the population bordering the Mediterranean Sea. It is considered a To help implement the Portfolio diet into clinical plant-based diet characterized by a high consumption practice, several patient and physician engagement of fruits, vegetables, (preferably unrefined), tools were created as a direct translation of the clinical legumes (including soy), nuts, and seeds; the use of practice guidelines. A Portfolio Diet infographic was olive oil as the main source of dietary fat for cooking developed in partnership with the University of and dressing; moderate consumption of wine within Toronto, St. Michael’s Hospital, and the Canadian ; and a low to moderate consumption of animal- Cardiovascular Society (CCS) along with a mobile- based foods, especially in form of poultry, fish, yogurt, based application (www.PortfolioDiet.app).238 and eggs.239 It is also low in red meat and processed meat, cream, sugar-sweetened beverages, and other PORTFOLIO DIET AND CARDIOMETABOLIC processed food. The peculiarity of the MedDiet lies in DISEASES the traditional lifestyle characterized by a healthy diet Despite the international consensus on the LDL-C where people eat together and enjoy the company, hypothesis and the evidence in support of the Portfolio perform physical activity, and regularly nap.239 Variants diet for LDL-C-and ASCVD risk reduction, the need for of the diet exist, depending on the characteristics of more research on harder CV outcomes remains. Large each Mediterranean country. Even so, for research RCTs on the effect of the Portfolio diet on the purposes it is referred to as the MedDiet and different progression of atherosclerosis are needed to assess tools to assess adherence, including screener whether the reductions in LDL-C and other established questionnaires and a priori and a posteriori scores, have cardiometabolic risk factors translate into reductions in been validated.240

38

FIGURE 20. PYRAMID OF THE MEDITERRANEAN DIET.

Source: Fundación Dieta Mediterránea (https://dietamediterranea.com/)

The MedDiet is considered an environmentally disease prevention. The MedDiet’s cardioprotective sustainable dietetic model, mainly due to the use of role was first hinted at in the mid-1900s by Ancel Keys proximity products with low environmental impact.241,242 in the Seven Countries Study249. Since then, many Interestingly, in 2010 UNESCO considered it to be an researchers have focused on studying the potential Intangible Cultural Heritage of Humanity,243 and it was health effects of this prominent diet. recognized by the 2015-2020 American dietary guidelines as an example of a healthy eating pattern.244 MEDITERRANEAN DIET AND However, evidence shows that adherence to the CARDIOMETABOLIC RISK FACTORS MedDiet is decreasing in many Mediterranean Evidence concerning the effect of the MedDiet on countries,245–248 with a clear trend towards a cardiometabolic risk factors is vast and mostly comes Westernized Diet, especially in young people. This is from clinical trials. The MedDiet reduces fasting plasma mainly due to the globalization process. glucose levels, systolic and diastolic blood pressure, and triglycerides levels,250 and increases concentrations The MedDiet is considered one of the more trustworthy of HDL-cholesterol by 0.19mg/dL in adults.250 It also diets, as there is a long track record of robust scientific improves endothelial function and reduces evidence on its benefits to quality of life, longevity, and inflammation, which are mediators of many

39 cardiometabolic diseases.251 In addition, the MedDiet MedDiet adherence and the risk of CVD.257 Strongly has beneficial effects on body adiposity despite being consistent results have been found. Greater adherence a high-fat diet. It is a useful tool to reduce waist to the MedDiet is associated with a lower risk of circumference250 and body weight, especially if it is developing total CVD and CVD mortality. Regarding the accompanied by caloric restriction and physical specific conditions of CVD, the existing evidence is also activity.252 These results have been reinforced by the substantial and aligned with previous findings. An DIRECT study253 and more recently by the PREDIMED- inverse association between increased adherence to Plus clinical trial. After 12 months of intervention, the the MedDiet and the risk of myocardial infarction (MI), preliminary results proved that an energy-restricted stroke, CHD, and heart failure has been demonstrated. MedDiet in addition to physical activity, promotion, and The reduction in the risk of these diseases ranges behavioural support reduces not only body weight and between 10% and 30%.183,257 To date, few clinical trials waist circumference, but also improves glucose have been conducted in this field, but the results that metabolism, lipid profiles, and markers of inflammation do exist are consistent and reinforce those from compared to a non-energy restricted MedDiet in observational studies. In 1999, The Lyon Diet Heart Study overweight/obese elderly individuals.254 The demonstrated an approximately 70% lower risk of aforementioned beneficial effects of the MedDiet have suffering recurrent MI in participants allocated to the also been reported in patients with T2D.255 Moreover, MedDiet compared to those following children of mothers that followed the MedDiet during recommendations close to the Step I diet of the pregnancy have been shown to have lower adiposity, American Heart Association.258 Similarly, in 2002, a study levels, and blood pressure, demonstrating with some concerns regarding the reliability of the data healthy effects in the offspring as well.256 reported that the intervention group following the Indo-MedDiet had a reduction in risk of non-fatal MI, MEDITERRANEAN DIET AND sudden cardiac death, and total cardiac endpoints CARDIOMETABOLIC DISEASES compared to the control group following the prudent The MedDiet can be considered one of the best dietary Step I diet.259 However, the biggest intervention study patterns that is best analysed in CVD and other performed to date is the PREDIMED-study, which also cardiometabolic diseases. Since the Seven Countries demonstrated a 30% lower risk of CVD in those study showed a lower rate of CHD mortality in participants following either a MedDiet enriched with populations living in Mediterranean countries,249 an extra-virgin olive oil or a MedDiet enriched with nuts, important number of observational studies have been compared to participants advised to follow a low-fat published evaluating the association between the control diet260 in elder individuals at high CVD risk.

40 A. B.

FIGURE 21 . PREDIMED STUDY: Kaplan-Meier estimates of the cumulative incidence of the primary end point (A; a composite of myocardial infarction, stroke and cardiovascular disease death) and total mortality (B) in the total study population from the PREDIMED study.

Abbreviations: CI, confidence interval; EVOO, extra virgin olive oil. Adapted from: R Estruch et al. N Engl J Med 2018;378:e34.

Although there is not as much evidence as with CVD, suggest the MedDiet as an appropriate approach to the MedDiet diet also appears to have beneficial effects prevent NAFLD and to delay the onset of its severe on other diseases. It’s been associated with a lower risk forms.266,267 Nevertheless, long-term trials are needed to of T2D development in large cohort studies as well as test the effects of this diet and physical activity on the in clinical trials, even without .261 The condition.267 diet may offer benefits in patients with established It is impossible to attribute the beneficial effects of the diabetes in terms of improving their glycaemic control MedDiet to a single constituent. Bioactive components and reducing their risk of complications associated with mainly present in plant-based foods (vegetables, fruits, this disease.262 It also seems to possess beneficial nuts, legumes, grains, extra virgin olive oil, and wine) act effects on metabolic syndrome prevalence and synergistically to affect various metabolic pathways. progression,263,264 which is important if we take into The MedDiet has beneficial effects on lipid metabolism, account that individuals with metabolic syndrome have insulin sensitivity, inflammation, oxidative stress, approximately twice as high risk of suffering CVD and a endothelial function, and gut microbiota, mainly five-fold higher risk of developing T2D than individuals through its unsaturated fatty acids composition, dietary without the syndrome.265 Additionally, the MedDiet has fibre, antioxidant vitamins, and several emerged as a potential tool for improving liver status phytochemicals.268 This explains the beneficial effects and to prevent and treat NAFLD. The best approach to not only on CVD but also on cognition,269,270 certain manage NAFLD is a lifestyle intervention based on a types of cancer,271 other chronic conditions,272 and total healthy diet and physical activity. The current scientific mortality.273 data based on cross-sectional and longitudinal studies

41

FIGURE 22 . POTENTIAL MECHANISMS BY WHICH THE MEDDIET COULD PROTECT AGAINST CARDIOVASCULAR DISEASES.

Abbreviations: CVD, cardiovascular disease; PUFAs, polyunsaturated fatty acids; MUFAs, monounsaturated fatty acids; SCFA, short chain fatty acids; TMAO, trimethyl amine N-oxide. Adapted from: Salas-Salvadó et al. Progress in Cardiovascular Diseases 2018: 61: 62–67.

42 NORDIC DIET The Nordic diet is quite similar to the MedDiet in that it emphasizes traditional and local foods from the Nordic countries: whole grains such as barley, rye and oats, berries, cabbages and root vegetables, fatty fish and legumes, and it is low in sweets and red meat. Instead of olive oil, the Nordic diet is rich in rapeseed oil (low in saturated fat, high in alpha-linolenic acid).

FIGURE 23 . THE NORDIC DIET.

Source: created by the Finnish Heart Association, the Finnish Diabetes Association and the University of Eastern Finland. Originally published in Public health nutrition 2013: 17. 1-9. 10.1017.

NORDIC DIET AND CARDIOMETABOLIC libitum Nordic diet (providing all meals and foods for the participants) with the subjects' usual Western diet RISK FACTORS for 6 weeks, found a 21% reduction in LDL cholesterol Several clinical trials indicate that the Nordic diet is on the Nordic diet.275 beneficial for cardiometabolic health. A 2019 meta- analysis of five RCTs (N=513) showed a significant A meta-analysis of four RCTs showed that the Nordic reduction in total cholesterol by 0.38 mmol/L and LDL diet lowered systolic blood pressure by ~4mmHg, and cholesterol by 0.30 mmol/L with the Nordic Diet.274 One diastolic blood pressure by ~2 mmHg.274 This level of 6-week RCT (NORDIET) conducted in Sweden in 88 reduction was confirmed by further studies.275,276 people with hypercholesterolemia, comparing an ad

43 While the Nordic Diet does not appear to cause diet compared to low adherers.285 In the EPIC-Potsdam significant changes in inflammatory biomarkers study, however, the Nordic diet only showed a stroke (including CRP)277, the SYSDIET study indicates that it benefit in men.286 does reduce the expression of genes responsible for The Nordic diet additionally yielded mixed results for inflammatory pathways in adipose tissue.278 T2D. The EPIC-Potsdam study showed no risk The Nordic diet has little effect on fasting plasma reduction,286 while the Danish Diet, Cancer and Health glucose, but does show reduced serum insulin cohort (N=55,060 with 7,366 T2D occurrences) concentrations.279 A single meal following Nordic diet demonstrated an inverse relationship between high guidelines can improve postprandial glucose and adherence to the Nordic diet and T2D. In this study, insulin responses in healthy volunteers.280 A 12-week women with highest adherence had a 25% reduced Nordic dietary intervention on participants with T2D T2D risk, while men had a 38% reduced risk.287 showed significant HbA1c reductions.281 In participants with components of metabolic In a 26-week RCT, participants with central obesity lost syndrome, a 12-week Nordic dietary intervention ~6.2 kg on the Nordic diet, vs. ~3 kg on the average lowered diastolic blood pressure by 4.4 mmHg. There Danish diet, without counting calories. A one-year was no difference in systolic blood pressure between follow-up showed a regain of 4.6 kg on the Nordic and Nordic intervention recipients and controls.288 The 1.1 kg regain on the average Danish diet.276, 282 In another Nordic diet may also benefit other components of study, participants with a high adherence to the Nordic metabolic syndrome, such as dyslipidemia,275 diet had lower waist circumferences than participants improvement in insulin resistance,279 and reduced waist with low adherence, independent of BMI.283 circumference.283

To our knowledge, at the time of writing, there are no intervention studies specifically examining the effects NORDIC DIET AND CARDIOMETABOLIC the Nordic diet may have on NAFLD. The Nordic diet DISEASES has, however, shown some positive effects on the Studies on the Nordic diet show mixed results on components of the metabolic syndrome. One study cardiometabolic outcomes. For example, the Swedish noted the presence of metabolic syndrome in ~65% of Women’s Lifestyle and Health cohort (N=43,310 with patients with confirmed NAFLD.289 Considering the 8,383 cases of heart disease) showed no association demonstrated potential benefit for metabolic between high adherence to the Nordic diet and syndrome, and the common co-existence of metabolic cardiovascular risk284, while a meta-analysis syndrome and NAFLD, future studies should elucidate demonstrated a 7% reduction in CVD risk, and a 13% the effects of the Nordic diet on the treatment and reduction in stroke risk.39 One study noted a reduced prevention of NAFLD. risk as high as 14% between high adherers to the Nordic

44 VEGETARIAN AND VEGAN DIETS Vegetarian diets emphasize the consumption of compared with non-vegetarians.292 Another meta- vegetables, fruits, soy, legumes, nuts, seeds and whole analysis of prospective cohort studies on vegetarian grains. Whereas vegetarian diets exclude all meat, diets showed a decreased risk of CHD mortality by 22% vegan diets exclude all animal-derived products. and incidence by 28%.182 A vegan diet centred on whole plant-based foods may even lead to reversal of VEGETARIAN DIETS AND heart disease, as evidenced by reduced size of CARDIOMETABOLIC DISEASES atherosclerotic plaques in coronary arteries.293 Vegetarian diets have been shown to reduce the risk of Vegetarian diets have also been shown to be CVD.290 In the EPIC study, vegetarians had a 32% lower protective against both haemorrhagic and ischemic risk of developing CHD compared to non- stroke.294 The risk of ischemic stroke risk increases by vegetarians.291 Systematic review and meta-analysis of 24% with every additional daily serving of meat.295 The eight prospective studies among Seventh-day figure below summarizes the findings of a meta- Adventists also shows vegetarian diets to be associated analysis of 7 prospective cohort studies, analysing the with a 40% reduced risk of CHD events and a 29% data from almost 200,000 participants. reduction in cerebral vascular disease events,

FIGURE 24. VEGETARIAN DIETS AND CARDIOVASCULAR DISEASE.

Abbreviations: CHD, coronary heart disease; CI, confidence interval; CVD, cardiovascular disease; NA, not applicable. Adapted from: Glenn AJ et al. Front. Nutr. 2019, 6.

Vegetarian diets have proven beneficial in both the circumference, triglycerides, total and LDL-C, blood prevention and treatment of T2D, leading to reductions glucose, and blood pressure.300 Additionally, vegetarian in haemoglobin A1c and fasting blood glucose levels.296 diets are protective against NAFLD even after When combined with exercise, they necessitate the adjustment for BMI.27 Vegetarian diets are associated reduction of anti-diabetic medications.297 Even without with a 21% lower risk of NAFLD compared with non- exercise, vegetarian diets are more effective in the vegetarian diets, even after adjustment for BMI. On the treatment of diabetes than a conventional diabetic other hand, replacing a serving of soy with a serving of diet.298 Finally, the prevalence of diabetes is cut in half meat or fish was associated with 12%-13% increased in vegans and vegetarians compared with non- risk.27 While weight loss may be one of the mechanisms vegetarians.299 behind improvements in NAFLD,30 plant-based diets low in saturated fat, high in fibre and unsaturated fatty Participants in the Adventist Health Study-2 following a acids, may have a positive impact on NAFLD even in the vegetarian diet had the lowest incidence of metabolic absence of weight loss.31 syndrome. Specifically, they had lower waist

45

63 VEGETARIAN DIETS AND and meta-analysis of 18 studies. In contrast, red meat intake is associated with higher CRP levels.64 CARDIOMETABOLIC RISK FACTORS Additionally, endothelial health can be maintained and A meta-analysis examining vegetarian diets and blood even improved with a plant-based diet. An inverse lipids on behalf of the American Heart Association relationship exists between consumption of saturated showed that LDL-C had a pooled lowering effect of ~6 fat (found primarily in animal foods and some tropical mg/dL (0.34mmol/L). This seemingly modest reduction oils) and flow-mediated dilation (a method of testing in LDL-C translates into a 10% reduction in risk of heart endothelial health).65 disease.301 In a cross-sectional analysis of the Epic Oxford Cohort, vegans had the lowest LDL-C and this One 16-week RCT demonstrated that a low-fat, plant- remained significant even after accounting for BMI. based diet was able to improve insulin sensitivity and beta-cell function in participants without diabetes.77 Another meta-analysis found that vegetarians have Improved insulin sensitivity has also been lower blood pressure than omnivores, independent of demonstrated in one study that replaced meat with soy salt intake, weight, and exercise. Depending on study products.303 Additionally, a meta-analysis demonstrated design, differences ranged from 4.8-6.9 mmHg systolic a 0.4% reduction in HbA1c, which is half the effect of reduction and a 2.2-4.7 mmHg diastolic reduction.128 metformin, an anti-diabetic medication.296 A more One study compared the blood pressures of updated meta-analysis of eight RCTs showed a endurance athletes, sedentary vegans, and sedentary reduction in HbA1c of 0.3%.181 Western diet consumers. Blood pressure was lowest in the vegan group (~104/62), followed by endurance Vegan diets are an effective weight control tool. In the runners (~122/72), and highest in the Western diet BROAD study, researchers demonstrated impressive control group (~132/70).302 It is important to note that weight loss results with a whole food, plant-based diet, when looking at populations with a normal blood instructing their participants to eat to satiation and not pressure, a further decrease would not be a desirable count calories. A whole food, plant-based diet lowered outcome. While a sub analysis of studies with baseline BMI by 4.4 points, and participants maintained that 74 systolic blood pressure ≥130 mm Hg revealed a clear weight loss at 12 months. A meta-analysis also decrease in both systolic (-4.1 mm Hg) and diastolic confirmed that vegetarian diets help with weight loss, blood pressure (-4.0 mm Hg), particularly on a vegan delineating that a vegan diet conferred the most weight diet303, studies in normotensive participants confirm that loss.75 Additionally, data from the Adventist Health vegetarian and vegan diets indeed do not cause such Study-2 show that those following a vegan diet are the blood-pressure-reducing effects in the normotensive only subset of people who average a healthy BMI, and population. that BMI increases in a stepwise fashion as more animal products enter the diet.76 Vegetarian diets are associated with lower CRP levels when used for at least two years, according to a review

46 CONCLUSION PLANT-BASED FOOD PATTERNS HAVE POSITIVE EFFECTS ON CARDIOMETABOLIC DISEASES AND THEIR RISK FACTORS

The present findings demonstrate that the Mediterranean, DASH, Portfolio, Nordic, and the vegetarian diets may have positive effects on the incidence of and mortality from various CVD outcomes. These diets can help to improve several cardiometabolic risk factors. Emphasizing the consumption of vegetables, fruits, soy, legumes, nuts, seeds and whole grains, these plant-based diets, may be recommended for cardiometabolic health.

FIGURE 25 . CHANGES IN BODY WEIGHT, LDL CHOLESTEROL, SYSTOLIC BLOOD PRESSURE AND HbA1c.

Abbreviations: LDL, low-density lipoprotein; HbA1c, glycosylated haemoglobin A1c. Adapted from: Kahleova H et al. Nutrients. 2019;11(9).

BENEFITS AND BARRIERS OF A participants liked their assigned diets. Interestingly, at six months, even if participants weren’t completely PLANT-BASED DIET adherent to their assigned vegan/vegetarian diets, they Public views of plant-based diets show overall still consumed less cholesterol and lost more weight 305 favourability. Australian researchers surveyed people than their counterparts. This study shows that it’s about their perceived benefits and barriers to plant- reasonable for doctors to recommend big changes to based diets. 70% of the 415 respondents recognized their patients: even patients who don’t fully comply with reduced saturated fat, increased fibre intake, and health recommendations are likely to see some health benefits as driver to follow plant-based diets. The most benefits. common barrier was lack of information, a factor that Finally, plant-based foods can likely be incorporated could be remedied by knowledgeable healthcare more into everyday meals without impacting food 304 providers and even the food industry. acceptability. One study demonstrated that replacing Another study examined adherence of participants 2/3 of the meat in a burrito bowl with vegetables and randomized to a vegan, vegetarian, pesco-vegetarian, legumes yielded the same acceptability to its student 307 semi-vegetarian, or an diet. Adherence was consumers as the original meat-heavy burrito bowls. equal across all diets, regardless of whether the

47 LINK BETWEEN DIET, GUT MICROBIOME DIVERSITY AND CARDIOMETABOLIC HEALTH

47 he gut microbiome consists of about a thousand diversity of the gut microbiome as well as SCFA- microbial species with around 160 species in the producing bacteria in the gut.315,316 Tlarge intestine of any individual. The combinations and abundances of species are hugely TRIMETHYLAMINE N-OXIDE variable from person to person. Some promote health, (TMAO) while others do not. Keeping these bacteria in balance Animal products such as cheese, fish, eggs, and meat is essential for good health. Observational studies of the are high in the compounds L-carnitine and choline. The gut microbiomes of healthy subjects and patients bacteria in the gut convert these compounds to suggest that the microbiome is associated with the trimethylamine (TMA). Afterward, TMA is converted into promotion of health and in the aetiology or trimethylamine n-oxide (TMAO) by the liver, which has development of a range of gastrointestinal diseases been shown to increase the risk of CVD.317 While a diet and disorders such as inflammatory bowel disease, rich in animal products has been linked to higher TMAO irritable bowel syndrome and colon cancer, and more recently in disease outside the gut namely obesity, levels, plant-based foods have the opposite effect and are associated with lower TMAO levels.328 diabetes and liver disease. Currently, there is not a great deal of consistency between studies in the specific types of bacteria involved. However, there is some BODY WEIGHT AND GUT consensus that microbiome diversity, i.e. having a wide MICROBIOME variety of different species in the gut is important for Plant-based diets promote a healthy weight. Studies good health and that loss of diversity is common in have suggested that people with excess body weight patients with these various diseases.308-310 tend to have less microbial diversity.316 A lack of Components of plant-based foods, especially dietary diversity has been linked to inflammatory diseases. fibre, are a major source of nutrients for gut bacteria Furthermore, overweight individuals tend to have more that metabolise them into short-chain fatty acids (SCFA) of the proinflammatory Firmicutes than anti- 316 – highly bioactive molecules that have been linked to a inflammatory Bacteroidetes. While animal-based wide variety of health benefits. diets tend to boost the proinflammatory Firmicutes population, eating plant-based foods builds up the anti- Increasing number of studies suggest that an effective inflammatory Bacteroidetes population, which can, in way of increasing microbial diversity and SCFA turn, help with weight loss. One study compared the production is to consume plant-based diets. A plant- diets of a Chinese population to an Indian population.319 based diet allows a higher availability of fibres which The Chinese population consumed significantly more cannot be digested by humans but are metabolized by animal products and fatty foods, while Indians the gut microbiota. consumed more whole grains and plant-based foods. The Indian population had almost four times the SHORT-CHAIN FATTY ACIDS amount of Bacteroidetes and a better Bacteroidetes-to- Fibre consumption increases the presence of beneficial Firmicutes ratio when compared to the Chinese. bacteria in the digestive tract that produce SCFAs.311 Another study compared Italian children, who ate a They are essential for maintaining good health and low-fibre Western diet high in animal products, sugar, preventing disease.312 Specifically, SCFAs improve body and fat, with children living in rural Africa, who weight, T2D, immunity, and inflammatory bowel consumed a lower-fat diet rich in starch, fibre, and disease.313,314 plant-based foods overall. African children had more than double the amount of Bacteroidetes and a higher In addition to fibre, plant protein, polyunsaturated and Bacteroidetes-to-Firmicutes ratio.320 monounsaturated fat, and polyphenols all increase the

49

FIGURE 26. EFFECT OF PLANT-BASED DIET VS. WESTERN DIET ON GUT BACTERIA.

Abbreviations: spp.: species pluralis. Adapted from Muralidharan J, et al J. Front Nutr. 2019;6:157.

50 IN CONCLUSION

51 KEY MESSAGES

 Cardiovascular disease (CVD) continues to be unsaturated fatty acids, low in carbohydrates, the leading cause of death worldwide. In rich in fibre, minerals, vitamins and other Europe, CVD accounts for 45% of all deaths. bioactive compounds such as polyphenols.

 Important behavioural factors associated with  Soybeans are high in protein and have a cardiometabolic disease risk include beneficial fat composition (low in saturates unhealthy diet, physical inactivity, tobacco and containing poly-unsaturated fatty acids). use, and excessive alcohol use. Diet can be Soy protein is a high-quality protein containing attributed to about 45.4% of all premature all the essential amino acids in sufficient deaths from CVD. quantities. Regular soy food consumption has been shown to have a significant and  Non-alcoholic fatty liver disease (NAFLD), a consistent cholesterol-lowering effect of 3 to disease closely related to CVD with a 5%. Beyond the effect on LDL, studies prevalence as high as 90% in morbidly obese indicated that soy foods can also lower blood persons. NAFLD is expected to become the pressure. leading cause of end-stage liver disease worldwide over the next few decades. NAFLD  Legumes are a good source of fibre and has as only recommended treatment the carbohydrates, and are considered a low- change of lifestyle (diet and physical glycaemic-index food. Legumes fit within a exercise). heart healthy diet.

 There are different forms of plant-based  Adherence to diets containing whole grains is eating patterns, from vegan over vegetarian associated with reduced incidence of to flexitarian-type diets. Plant-based eating diabetes and CVD and improved glycaemic does not necessarily exclude all animal control, blood pressure and lipids. products but puts plant-based foods such as  International dietary guidelines and clinical fruits, vegetables, soy, legumes, wholegrains, practice guidelines for diabetes and heart nuts, seeds, vegetable oils and plant-based health are universal in their recommendation alternatives to meat and dairy at the core of to consume fruits and vegetables (at least the diet. 400g per day).  Plant-based diets like Mediterranean diet,  Plant-based foods and eating patterns are Nordic diet, Portfolio diet, DASH diet, and important in maintaining healthy blood vegetarian and vegan diets have several cholesterol levels and subsequently a healthy characteristics that may contribute to their role heart. in cardiometabolic health. These include high fibre content, low caloric density, high  Evidence is accumulating to suggest that nutrient density, lower saturated fat, blood pressure may also be lower in those beneficial fatty acid composition (higher in following plant-based diets. unsaturated fats) and anti-inflammatory  In addition, specific components found compounds. intrinsically in plant foods may also work  Nut consumption is linked to reduced risk of together to bring further cardiometabolic CVD and lower prevalence of T2D. Nuts have benefits. a beneficial nutritional profile: high in

52 ENVIRONMENTAL BENEFITS Report from 2019.330 This report provides the first scientific targets for a Planetary Health diet from a On top of the health benefits, a plant-based diet is also sustainable food production system that operates at the core of more sustainable diets. To stay within the within planetary boundaries for food. It specifically planetary boundaries, a combination of major dietary recommends ’diets consisting of a variety of plant- change to more plant-based foods, improved food based foods, with low amounts of animal-based foods, production, and reduced food waste during all steps of refined grains, highly processed foods, and added the food chain will be needed. sugars, and with unsaturated rather than saturated fats’. Several food-based dietary guidelines advise people to The authors highlight the need to reduce, by more than eat more plant-based foods not only for health but also 50%, the global consumption of foods such as red meat for environmental considerations. Sweden was the first and sugar and increase the consumption of nuts, fruits, country in 2015 to link dietary health with planetary vegetables, soy, legumes by more than two-fold, with health.321 Other countries followed, including United global targets being applied locally to reflect regional Kingdom, Belgium, Germany and the Netherlands.322- differences in needs. Overall, they concluded that to 324,328 The general message was that less red meat stay within planetary boundaries, a combination of should be eaten and more plant-based foods. The major dietary change, improved food production United States Dietary Guidelines Advisory Committee through enhanced agriculture and technology (DGAC) for example, advocated strongly for less red changes, and reduced food waste during all steps of meat and for environmental considerations. In fact, one the food chain from production to consumption of the three diets put forward to the American people (including farmers, processors, supermarkets, was a vegetarian diet, quite unusual when looking at restaurants, and people at home) will be needed (for earlier recommendations.244 This change has been more info see Alpro Foundations scientific update driven by the accumulation of scientific evidence in the ‘More plant-based eating for the planet’ (2019)). years since the last guideline was issued in 2015. Canada Just recently the same authors analysed the health and followed suit with its Food Guide which also mentions environmental implications of adhering to national food environmental reasons as a driver for change. The based dietary guidelines from 85 countries and Guide’s food plate was also overhauled, to a plate compared these with global health and environmental largely consisting of plant-based foods.329 The focus is targets.331 They concluded that national guidelines now on plant-based foods, especially sources of plant could be both healthier and more sustainable if they protein. were closer to the EAT Planetary Health diet which is a Over the last few years, a significant amount of new predominantly plant-based diet. The authors are calling evidence has emerged which support the need, from a national health authorities to revise their national dietary sustainability perspective, to transition towards plant- guidelines to integrate sustainability issues more and based diets. One of the most notable and influential reinforce the health benefits. scientific papers is that of the EAT-Lancet Commission

The EAT Foundation is calling national health authorities to update their national dietary guidelines taking health and environmental benefits into account. Limiting the consumption of animal-derived foods, in particular beef and dairy, has the greatest potential for increasing the environmental sustainability of dietary guidelines. Increasing the intake of whole grains, fruits, vegetables, nuts, seeds, and legumes, while reducing the intake of red and processed meat, and attaining balanced energy intake were associated with most of the health benefits.

53 References:

1. Cardiovascular diseases (CVDs). Accessed March 19, 2020. 18. AHA 2019 Heart Disease and Stroke Statistics. American College of https://www.who.int/news-room/fact-sheets/detail/cardiovascular- Cardiology. Accessed April 9, 2020. diseases-(cvds) http%3a%2f%2fwww.acc.org%2flatest-in-cardiology%2ften-points- to-remember%2f2019%2f02%2f15%2f14%2f39%2faha-2019-heart- 2. Townsend N, Wilson L, Bhatnagar P, Wickramasinghe K, Rayner M, disease-and-stroke-statistics Nichols M. Cardiovascular disease in Europe: epidemiological update 2016. Eur Heart J. 2016;37(42):3232-3245. 19. Donkor ES. Stroke in the 21st Century: A Snapshot of the Burden, doi:10.1093/eurheartj/ehw334 Epidemiology, and Quality of Life. Stroke Res Treat. 2018;2018. doi:10.1155/2018/3238165 3. Micha R, Peñalvo J. Association Between Dietary Factors and Mortality From Heart Disease, Stroke, and Type 2 Diabetes in the 20. Kuźma E, Lourida I, Moore SF, Levine DA, Ukoumunne OC, Llewellyn United States. JAMA. 2017;317(9):912-924. DJ. Stroke and dementia risk: A systematic review and meta-analysis. Alzheimer’s & Dementia. 2018;14(11):1416-1426. 4. Roth GA, Johnson C, Abajobir A, et al. Global, Regional, and National doi:10.1016/j.jalz.2018.06.3061 Burden of Cardiovascular Diseases for 10 Causes, 1990 to 2015. J Am Coll Cardiol. 2017;70(1):1-25. doi:10.1016/j.jacc.2017.04.052 21. Saklayen MG. The Global Epidemic of the Metabolic Syndrome. Curr Hypertens Rep. 2018;20(2). doi:10.1007/s11906-018-0812-z 5. CVD Statistics. Accessed May 28, 2020. http://www.ehnheart.org/cvd-statistics.html 22. Scuteri A, Laurent S, Cucca F, et al. Metabolic syndrome across Europe: different clusters of risk factors. Eur J Prev Cardiol. 6. Virmani R, Burke AP, Farb A, Kolodgie FD. Pathology of the 2015;22(4):486-491. doi:10.1177/2047487314525529 Vulnerable Plaque. J Am Coll Cardiol. 2006;47 (8S):C13-C18. doi:10.1016/j.jacc.2005.10.065 23. Suliga E, Kozieł D, Głuszek S. Prevalence of metabolic syndrome in normal weight individuals. Ann Agric Environ Med. 2016;23(4):631- 7. What can I do to avoid a heart attack or a stroke? Accessed May 28, 635. doi:10.5604/12321966.1226858 2020. https://www.who.int/news-room/q-a-detail/what-can-i-do- to-avoid-a-heart-attack-or-a-stroke 24. Dowman JK, Tomlinson JW, Newsome PN. Pathogenesis of non- alcoholic fatty liver disease. QJM. 2010;103(2):71-83. 8. CDC. Know Your Risk for Heart Disease | cdc.gov. Centers for doi:10.1093/qjmed/hcp158 Disease Control and Prevention. Published December 9, 2019. Accessed April 10, 2020. 25. Pais R, Barritt AS, Calmus Y, et al. NAFLD and liver transplantation: https://www.cdc.gov/heartdisease/risk_factors.htm Current burden and expected challenges. J Hepatol. 2016;65(6):1245-1257. doi:10.1016/j.jhep.2016.07.033 9. Strong JP, McGill HC. The Natural History of Coronary Atherosclerosis. Am J Pathol. 1962;40(1):37-49. 26. Younossi Z, Anstee QM, Marietti M, et al. Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nat Rev 10. Enos WF, Holmes RH, Beyer J. Coronary disease among United Gastroenterol Hepatol. 2018;15(1):11-20. doi:10.1038/nrgastro.2017.109 States soldiers killed in action in Korea: preliminary report. JAMA. 1953;152(12):1090-1093. doi:10.1001/jama.1953.03690120006002 27. Chiu TH, Lin M-N, Pan W-H, Chen Y-C, Lin C-L. Vegetarian diet, food substitution, and nonalcoholic fatty liver. Tzu Chi Med J. 11. Manifestations of coronary atherosclerosis in young trauma 2018;30(2):102-109. doi:10.4103/tcmj.tcmj_109_17 victims—An autopsy study | Elsevier Enhanced Reader. doi:10.1016/0735-1097(93)90050-B 28. Razavi Zade M, Telkabadi MH, Bahmani F, Salehi B, Farshbaf S, Asemi Z. The effects of DASH diet on weight loss and metabolic status in 12. Kaplan H, Thompson RC, Trumble BC, et al. Coronary atherosclerosis adults with non-alcoholic fatty liver disease: a randomized clinical in indigenous South American Tsimane: a cross-sectional cohort trial. Liver Int. 2016;36(4):563-571. doi:10.1111/liv.12990 study. . 2017;389(10080):1730-1739. doi:10.1016/S0140- 6736(17)30752-3 29. Plaz Torres MC, Aghemo A, Lleo A, et al. Mediterranean Diet and NAFLD: What We Know and Questions That Still Need to Be 13. Mata-Cases M, Casajuana M, Franch-Nadal J, et al. Direct medical Answered. Nutrients. 2019;11(12). doi:10.3390/nu11122971 costs attributable to type 2 diabetes mellitus: a population-based study in Catalonia, Spain. Eur J Health Econ. 2016;17(8):1001-1010. 30. Wong VW-S, Chan RS-M, Wong GL-H, et al. Community-based doi:10.1007/s10198-015-0742-5 lifestyle modification programme for non-alcoholic fatty liver disease: a randomized controlled trial. J Hepatol. 2013;59(3):536-542. 14. The Burden of Cardiovascular Disease in Patients with Diabetes. doi:10.1016/j.jhep.2013.04.013 AJMC. Accessed March 20, 2020. https://www.ajmc.com/journals/supplement/2018/reducing-rick- 31. Riazi K, Raman M, Taylor L, Swain MG, Shaheen AA. Dietary Patterns cv-patients-with-diabetes/the-burden-of-cardiovascular-disease-in- and Components in Nonalcoholic Fatty Liver Disease (NAFLD): What patients-with-diabetes Key Messages Can Health Care Providers Offer? Nutrients. 2019;11(12). doi:10.3390/nu11122878 15. Study: The burden of diabetes in Europe. Accessed May 28, 2020. https://www.efpia.eu/news-events/the-efpia-view/blog- 32. Yusuf Salim, Reddy Srinath, Ôunpuu Stephanie, Anand Sonia. Global articles/120125-study-the-burden-of-diabetes-in-europe/ Burden of Cardiovascular Diseases. Circulation. 2001;104(22):2746- 2753. doi:10.1161/hc4601.099487 16. Soler EP, Ruiz VC. Epidemiology and Risk Factors of Cerebral Ischemia and Ischemic Heart Diseases: Similarities and Differences. 33. Roser M, Ritchie H. Burden of Disease. Our World in Data. Published Curr Cardiol Rev. 2010;6(3):138-149. doi:10.2174/157340310791658785 online January 25, 2016. Accessed March 23, 2020. https://ourworldindata.org/burden-of-disease 17. Mir M, Albaradie R, Alhassanavi M. Pathophysiology of Strokes. In: ; 2014:25-80.

54 34. Derbyshire EJ. Flexitarian Diets and Health: A Review of the 51. Steffen LM, Kroenke CH, Yu X, et al. Associations of plant food, dairy Evidence-Based Literature. Front Nutr. 2017;3. product, and meat intakes with 15-y incidence of elevated blood doi:10.3389/fnut.2016.00055 pressure in young black and white adults: the Coronary Artery Risk Development in Young Adults (CARDIA) Study. Am J Clin Nutr. 35. Pescatarian | Definition of Pescatarian by Lexico. Accessed February 2005;82(6):1169-1177. doi:10.1093/ajcn/82.6.1169 21, 2020. https://www.lexico.com/en/definition/pescatarian 52. Appel, L.J., et al., Effects of protein, monounsaturated fat, and 36. Lacto-Ovo-Vegetarian | Definition of Lacto-Ovo-Vegetarian by carbohydrate intake on blood pressure and serum lipids: results of Lexico. Accessed February 21, 2020. the OmniHeart randomized trial. JAMA, 2005. 294(19): p. 2455-64. https://www.lexico.com/en/definition/lacto-ovo-vegetarian 53. Chan Q, Stamler J, Brown IJ, et al. Relation of raw and cooked 37. Vegan | Definition of Vegan by Lexico. Accessed February 21, 2020. vegetable consumption to blood pressure: the INTERMAP Study. J https://www.lexico.com/en/definition/vegan Hum Hypertens. 2014;28(6):353-359. doi:10.1038/jhh.2013.115

38. What Is a Whole Food, Plant-Based Diet? Center for Nutrition 54. Yokoyama Y, Tsubota K, Watanabe M. Effects of vegetarian diets on Studies. Published August 8, 2018. Accessed March 20, 2020. blood pressure. Nutrition and Dietary Supplements. 2016. https://nutritionstudies.org/what-is-a-whole-food-plant-based-diet/ doi:10.2147/NDS.S74715

39. Kahleova H, Salas-Salvadó J, Rahelić D, Kendall CW, Rembert E, 55. WHO | Raised cholesterol. WHO. Accessed March 24, 2020. Sievenpiper JL. Dietary Patterns and Cardiometabolic Outcomes in https://www.who.int/gho/ncd/risk_factors/cholesterol_text/en/ Diabetes: A Summary of Systematic Reviews and Meta-Analyses. Nutrients. 2019;11(9). doi:10.3390/nu11092209 56. CDC. High Cholesterol Facts. Centers for Disease Control and Prevention. Published January 31, 2020. Accessed March 24, 2020. 40. CDC. Sugar Sweetened Beverage Intake. Centers for Disease https://www.cdc.gov/cholesterol/facts.htm Control and Prevention. Published October 23, 2018. Accessed March 20, 2020. https://www.cdc.gov/nutrition/data- 57. Bantwal G, George B. Low density Lipoprotein cholesterol target: statistics/sugar-sweetened-beverages-intake.html Changing goal posts. Indian J Endocrinol Metab. 2012;16(Suppl 2):S233-S235. doi:10.4103/2230-8210.104047 41. Ornish D, Scherwitz LW, Billings JH, et al. Intensive Lifestyle Changes for Reversal of Coronary Heart Disease. JAMA. 1998; 280(23):2001. 58. Mudau M, Genis A, Lochner A, Strijdom H. Endothelial dysfunction: doi: 10.1001/jama.280.23.2001. the early predictor of atherosclerosis. Cardiovasc J Afr. 2012;23(4):222-231. doi:10.5830/CVJA-2011-068 42. Satija A, Bhupathiraju SN, Spiegelman D, et al. Healthful and unhealthful plant-based diets and the risk of coronary heart disease 59. Vogel RA, Corretti MC, Plotnick GD. Effect of a Single High-Fat Meal in US adults. J Am Coll Cardiol. 2017;70(4):411-422. on Endothelial Function in Healthy Subjects. Am J of Cardiology. doi:10.1016/j.jacc.2017.05.047 1997;79(3):350-354. doi:10.1016/S0002-9149(96)00760-6

43. Portfolio Dietary Pattern and Cardiovascular Disease: A Systematic 60. Tuso P, Stoll SR, Li WW. A Plant-Based Diet, Atherogenesis, and Review and Meta-analysis of Controlled Trials | Elsevier Enhanced Coronary Artery Disease Prevention. Perm J. 2015;19(1):62-67. Reader. doi:10.1016/j.pcad.2018.05.004 doi:10.7812/TPP/14-036

44. Kerley CP. A Review of Plant-based Diets to Prevent and Treat Heart 61. Willerson James T., Ridker Paul M. Inflammation as a Cardiovascular Failure. Card Fail Rev. 2018;4(1):54-61. doi:10.15420/cfr.2018:1:1 Risk Factor. Circulation. 2004;109(21_suppl_1):II-2. doi:10.1161/01.CIR.0000129535.04194.38 45. Wolf-Maier K, Cooper RS, Banegas JR, et al. Hypertension prevalence and blood pressure levels in 6 European countries, 62. Ridker PM, Hennekens CH, Buring JE, Rifai N. C-Reactive Protein and Canada, and the United States. JAMA. 2003;289(18):2363-2369. Other Markers of Inflammation in the Prediction of Cardiovascular doi:10.1001/jama.289.18.2363 Disease in Women. N Engl J Med. 2000;342(12):836-843. doi:10.1056/NEJM200003233421202 46. Comparison of the ACC/AHA and ESC/ESH Hypertension Guidelines. American College of Cardiology. Accessed May 29, 63. Haghighatdoost F, Bellissimo N, Totosy de Zepetnek JO, Rouhani 2020. http%3a%2f%2fwww.acc.org%2flatest-in- MH. Association of vegetarian diet with inflammatory biomarkers: a cardiology%2farticles%2f2019%2f11%2f25%2f08%2f57%2fcomparison systematic review and meta-analysis of observational studies. Public -of-the-acc-aha-and-esc-esh-hypertension-guidelines Health Nutr. 2017;20(15):2713-2721. doi:10.1017/S1368980017001768

17. New ACC/AHA High Blood Pressure Guidelines Lower Definition of 64. Ley SH, Sun Q, Willett WC, et al. Associations between red meat Hypertension. American College of Cardiology. Accessed March 13, intake and biomarkers of inflammation and glucose metabolism in 2020. http%3a%2f%2fwww.acc.org%2flatest-in- women. Am J Clin Nutr. 2014;99(2):352-360. cardiology%2farticles%2f2017%2f11%2f08%2f11%2f47%2fmon-5pm- doi:10.3945/ajcn.113.075663 bp-guideline-aha-2017 65. Comparative Effects of 3 Popular Diets on Lipids, Endothelial 48. Williams B, Mancia G, Spiering W, et al. 2018 ESC/ESH Guidelines for Function and C-Reactive Protein during Weight Maintenance. J Am the management of arterial hypertension. Eur Heart J. Diet Assoc. 2009;109(4):713-717. doi:10.1016/j.jada.2008.12.023 2018;39(33):3021-3104. doi:10.1093/eurheartj/ehy339 66. Ridker Paul M. Clinical Application of C-Reactive Protein for 49. Bolad I, Delafontaine P. Endothelial dysfunction: its role in Cardiovascular Disease Detection and Prevention. Circulation. hypertensive coronary disease. Curr Opin Cardiol. 2005;20(4):270- 2003;107(3):363-369. doi:10.1161/01.CIR.0000053730.47739.3C 274. 67. Obesity and overweight. Accessed March 25, 2020. 50. Drazner Mark H. The Progression of Hypertensive Heart Disease. https://www.who.int/news-room/fact-sheets/detail/obesity-and- Circulation. 2011;123(3):327-334. overweight doi:10.1161/CIRCULATIONAHA.108.845792

55 68. Aronne LJ, Isoldi KK. Overweight and obesity: key components of 85. Albert CM, Gaziano JM, Willett WC, Manson JE. Nut Consumption cardiometabolic risk. Clin Cornerstone. 2007;8(3):29-37. and Decreased Risk of Sudden Cardiac Death in the Physicians’ doi:10.1016/s1098-3597(07)80026-3 Health Study. Arch Intern Med. 2002;162(12):1382. doi:10.1001/archinte.162.12.1382 69. Guerre-Millo M. Adipose tissue hormones. J Endocrinol Invest. 2002;25(10):855-861. doi:10.1007/BF03344048 86. Heffron SP, Rockman CB, Gianos E, Guo Y, Berger JS. Greater frequency of nut consumption is associated with lower prevalence 70. Booth A, Magnuson A, Fouts J, Foster MT. Adipose tissue: an of peripheral arterial disease. Prev Med. 2015;72:15-18. endocrine organ playing a role in metabolic regulation. doi:10.1016/J.YPMED.2014.12.014 Horm Mol Biol Clin Investig. 2016;26(1):25-42. doi:10.1515/hmbci-2015- 0073 87. Larsson SC, Drca N, Björck M, Bäck M, Wolk A. Nut consumption and incidence of seven cardiovascular diseases. Heart (British Cardiac 71. Bosomworth NJ. Normal-weight central obesity. Can Fam Physician. Society). 2018;104(19):1615-1620. doi:10.1136/heartjnl-2017-312819 2019;65(6):399-408. 88. Estruch R, Ros E, Salas-Salvadó J, et al. Primary Prevention of 72. McKeown NM, Troy LM, Jacques PF, Hoffmann U, O’Donnell CJ, Fox Cardiovascular Disease with a Mediterranean Diet Supplemented CS. Whole- and refined-grain intakes are differentially associated with Extra-Virgin Olive Oil or Nuts. N Engl J Med. 2018;378(25):e34. with abdominal visceral and subcutaneous adiposity in healthy doi:10.1056/NEJMoa1800389 adults: the Framingham Heart Study12345. Am J Clin Nutr. 2010;92(5):1165-1171. doi:10.3945/ajcn.2009.29106 89. Ruiz-Canela M, Estruch R, Corella D, Salas-Salvadó J, Martínez- González MA. Association of Mediterranean diet with peripheral 73. Wang Y, Beydoun M. Meat consumption is associated with obesity artery disease: the PREDIMED randomized trial. JAMA. 2014;311(4):415- and central obesity among US adults. Int J Obes (Lond). 417. doi:10.1001/jama.2013.280618 2009;33(6):621-628. doi:10.1038/ijo.2009.45 90. Guasch-Ferré M, Liu X, Malik VS, et al. Nut Consumption and Risk of 74. Wright N, Wilson L, Smith M, Duncan B, McHugh P. The BROAD Cardiovascular Disease. J Am Coll Cardiol. 2017;70(20):2519-2532. study: A randomised controlled trial using a whole food plant- doi:10.1016/j.jacc.2017.09.035 based diet in the community for obesity, ischaemic heart disease or diabetes. Nutr & Diabetes. 2017;7(3):e256-e256. 90b. Pan A, Sun Q, Manson JE, Willett WC, Hu FB. Walnut consumption is doi:10.1038/nutd.2017.3 associated with lower risk of type 2 diabetes in women. J Nutr. 2013;143(4):512-518. doi:10.3945/jn.112.172171 75. Huang R-Y, Huang C-C, Hu FB, Chavarro JE. Vegetarian Diets and Weight Reduction: a Meta-Analysis of Randomized Controlled Trials. 91. Ibarrola-Jurado N, Bulló M, Guasch-Ferré M, et al. Cross-Sectional J Gen Intern Med. 2016;31(1):109-116. doi:10.1007/s11606-015-3390-7 Assessment of Nut Consumption and Obesity, Metabolic Syndrome and Other Cardiometabolic Risk Factors: The PREDIMED Study. PLoS 76. Tonstad S, Butler T, Yan R, Fraser GE. Type of Vegetarian Diet, Body One. 2013;8(2). doi:10.1371/journal.pone.0057367 Weight, and Prevalence of Type 2 Diabetes. Diabetes Care. 2009;32(5):791-796. doi:10.2337/dc08-1886 92. Sabaté J, Oda K, Ros E. Nut consumption and blood lipid levels: a pooled analysis of 25 intervention trials. Arch Intern Med. 77. Kahleova H, Tura A, Hill M, Holubkov R, Barnard N. A Plant-Based 2010;170(9):821-827. doi:10.1001/archinternmed.2010.79 Dietary Intervention Improves Beta-Cell Function and Insulin Resistance in Overweight Adults: A 16-Week Randomized Clinical 93. Morgillo S, Hill AM, Coates AM. The Effects of Nut Consumption on Trial. Nutrients. 2018;10(2):189. doi:10.3390/nu10020189 Vascular Function. Nutrients. 2019;11(1). doi:10.3390/nu11010116

78. Intramyocellular lipid concentrations are correlated with insulin 94. Hernández-Alonso P, Camacho-Barcia L, Bulló M, Salas-Salvadó J. sensitivity in humans: a 1H NMR spectroscopy study | SpringerLink. Nuts and Dried Fruits: An Update of Their Beneficial Effects on Type Accessed April 3, 2020. 2 Diabetes. Nutrients. 2017;9((7)):pii: E673. doi:10.3390/nu9070673 https://link.springer.com/article/10.1007%2Fs001250051123 95. Muralidharan J, Galiè S, Hernández-Alonso P, Bulló M, Salas-Salvadó 79. St-Onge M-P, Newcomer BR, Buchthal S, et al. Intramyocellular lipid J. Plant-Based Fat, Dietary Patterns Rich in Vegetable Fat and Gut content is lower with a low-fat diet than with high-fat diets, but that Microbiota Modulation. Frontiers in Nutrition. 2019;6. may not be relevant for health. Am J Clin Nutr. 2007;86(5):1316-1322. doi:10.3389/fnut.2019.00157 doi:10.1093/ajcn/86.5.1316 96. Li H, Li X, Yuan S, Jin Y, Lu J. Nut consumption and risk of metabolic 80. Acosta-Montaño P, García-González V.Effects of Dietary Fatty Acids syndrome and overweight/obesity: A meta-analysis of prospective in Pancreatic Beta Cell Metabolism, Implications in Homeostasis. cohort studies and randomized trials. Nutr Metab. 2018;15(1):1-10. Nutrients 2018;10(4):393. doi: 10.3390/nu10040393. doi:10.1186/s12986-018-0282-y

97. Salas-Salvado J, Guasch-Ferre M, Bullo M, Sabate J. Nuts in the 81. Evert AB, Dennison M, Gardner CD, et al. Nutrition Therapy for Adults prevention and treatment of metabolic syndrome. Am J Clin Nutr With Diabetes or Prediabetes: A Consensus Report. Dia Care. 2014;100(Supplement_1):399S-407S. doi:10.3945/ajcn.113.071530 2019;42(5):731-754. doi:10.2337/dci19-0014 98. Flores-Mateo G, Rojas-Rueda D, Basora J, Ros E, Salas-Salvadó J. Nut 82. Ros E, Mataix J. Fatty acid composition of nuts--implications for intake and adiposity: meta-analysis of clinical trials. Am J Clin Nutr n. cardiovascular health. Br J N.utr 2006;96 Suppl 2:S29-35. 2013;97(6):1346-1355. doi:10.3945/ajcn.111.031484 83. Segura R, Javierre C, Lizarraga MA, Ros E. Other relevant 99. Babio N, Toledo E, Estruch R, et al. Mediterranean diets and components of nuts: phytosterols, folate and minerals. Br J N.utr. metabolic syndrome status in the PREDIMED randomized trial. CMAJ. 2006;96 Suppl 2:S36-44. 2014;186(17):E649-57. doi:10.1503/cmaj.140764 84. Kim Y, Keogh JB, Clifton PM. Does Nut Consumption Reduce 100. De Souza RGM, Schincaglia RM, Pimente GD, Mota JF. Nuts and Mortality and/or Risk of Cardiometabolic Disease? An Updated human health outcomes: A systematic review. Nutrients. 2017;9(12). Review Based on Meta-Analyses. Int J Environ Res Public Health doi:10.3390/nu9121311 2019;16(24):4957. doi:10.3390/ijerph16244957

56 101. Messina M. Soy and Health Update: Evaluation of the Clinical and 117. Food Labeling: Health Claims; Soy Protein and Coronary Heart Epidemiologic Literature. Nutrients. 2016;8(12). Disease. 2017. p. 50324-46 (23 pages). doi:10.3390/nu8120754 118. Blanco Mejia S, Messina M, Li SS, et al. A Meta-Analysis of 46 Studies 102. Hughes GJ, Ryan DJ, Mukherjea R, Schasteen CS. Protein Identified by the FDA Demonstrates that Soy Protein Decreases digestibility-corrected scores (PDCAAS) for soy protein Circulating LDL and Total Cholesterol Concentrations in Adults. J isolates and concentrate: criteria for evaluation. J Agric Food Chem. Nutr. 2019;149(6):968-981. doi:10.1093/jn/nxz020 2011;59(23):12707-12712. doi:10.1021/jf203220v 119. Jenkins DJA, Mirrahimi A, Srichaikul K, et al. Soy protein reduces 103. Cao Z-H, Green-Johnson JM, Buckley ND, Lin Q-Y. Bioactivity of soy- serum cholesterol by both intrinsic and food displacement based fermented foods: A review. Biotechnol Adv. 2019;37(1):223- mechanisms. J Nutr. 2010;140(12):2302S-2311S. 238. doi:10.1016/j.biotechadv.2018.12.001 doi:10.3945/jn.110.124958

104. Messina M, Nagata C, Wu AH. Estimated Asian adult soy protein and 120. Sirtori CR, Pazzucconi F, Colombo L, Battistin P, Bondioli A, isoflavone intakes. Nutr Cancer. 2006;55(1):1-12. Descheemaeker K. Double-blind study of the addition of high- doi:10.1207/s15327914nc5501_1 protein soya v. cows’ milk to the diet of patients with severe hypercholesterolaemia and resistance to or intolerance of statins. Br 105. Macrotrends. Japan Life Expectancy 1950-2020 [Access Date: May J Nutr. 1999;82(2):91-96. 29 2020]. Available from: https://www.macrotrends.net/countries/JPN/japan/life-expectancy. 120b. Scientific Opinion on the substantiation of health claims related to the replacement of mixtures of saturated fatty acids (SFAs) as 106. W.H.O. Japan [Access Date: May 29 2020]. Available from: present in foods or diets with mixtures ofmonounsaturated fatty https://www.who.int/countries/jpn/en/. acids (MUFAs)and/or mixtures of polyunsaturated fatty acids (PUFAs),and maintenance of normal blood LDL-cholesterol 107. Reiser R. Saturated fat in the diet and serum cholesterol concentrations (ID 621, 1190, 1203, 2906, 2910, 3065)pursuant to concentration: a critical examination of the literature. Am J Clin Nutr. Article 13(1) of Regulation (EC) No 1924/2006 EFSA Journal. 1973;26(5):524-555. doi:10.1093/ajcn/26.5.524 2011;9(4):2069. doi:10.2903/j.efsa.2011.2069 108. Sirtori CR, Agradi E, Conti F, Mantero O, Gatti E. Soybean-protein 121. Jenkins DJA, Kendall CWC, Faulkner D, et al. A dietary portfolio diet in the treatment of type-II hyperlipoproteinaemia. Lancet. approach to cholesterol reduction: combined effects of plant 1977;1(8006):275-277. doi:10.1016/s0140-6736(77)91823-2 sterols, vegetable proteins, and viscous fibers in 109. Anderson JW, Johnstone BM, Cook-Newell ME. Meta-analysis of the hypercholesterolemia. Metab Clin Exp. 2002;51(12):1596-1604. effects of soy protein intake on serum lipids. N Engl J Med. doi:10.1053/meta.2002.35578 1995;333(5):276-282. doi:10.1056/NEJM199508033330502 122. Jenkins DJA, Kendall CWC, Marchie A, et al. Effects of a dietary 110. Food labeling: health claims; soy protein and coronary heart portfolio of cholesterol-lowering foods vs lovastatin on serum lipids disease. Food and Drug Administration, HHS. Final rule. Fed Regist. and C-reactive protein. JAMA. 2003;290(4):502-510. 1999;64(206):57700-57733. doi:10.1001/jama.290.4.502

111. Health Canada. Summary of Health Canada’s Assessment of a 123. Jenkins DJA, Jones PJH, Lamarche B, et al. Effect of a dietary portfolio Health Claim about Soy Protein and Cholesterol Lowering March of cholesterol-lowering foods given at 2 levels of intensity of dietary 2015 [Access Date: June 11 2020]. Available from: advice on serum lipids in hyperlipidemia: a randomized controlled https://www.canada.ca/en/health-canada/services/food- trial. JAMA. 2011;306(8):831-839. doi:10.1001/jama.2011.1202 nutrition/food-labelling/health-claims/assessments/summary- 124. Jenkins DJA, Kendall CWC, Faulkner DA, et al. Assessment of the assessment-health-claim-about-protein-cholesterol-lowering.html. longer-term effects of a dietary portfolio of cholesterol-lowering 112. Taku K, Umegaki K, Sato Y, Taki Y, Endoh K, Watanabe S. Soy foods in hypercholesterolemia. Am J Clin Nutr. 2006;83(3):582-591. isoflavones lower serum total and LDL cholesterol in humans: a doi:10.1093/ajcn.83.3.582 meta-analysis of 11 randomized controlled trials. Am J Clin Nutr. 125. Jenkins DJA, Kendall CWC, Marchie A, et al. The effect of combining 2007;85(4):1148-1156. doi:10.1093/ajcn/85.4.1148 plant sterols, soy protein, viscous fibers, and almonds in treating 113. Weggemans RM, Trautwein EA. Relation between soy-associated hypercholesterolemia. Metab Clin Exp. 2003;52(11):1478-1483. isoflavones and LDL and HDL cholesterol concentrations in humans: doi:10.1016/s0026-0495(03)00260-9 a meta-analysis. Eur J Clin Nutr. 2003;57(8):940-946. 126. Chiavaroli L, Nishi SK, Khan TA, et al. Portfolio Dietary Pattern and doi:10.1038/sj.ejcn.1601628 Cardiovascular Disease: A Systematic Review and Meta-analysis of 114. Harland JI, Haffner TA. Systematic review, meta-analysis and Controlled Trials. Prog Cardiovasc Dis. 2018;61(1):43-53. regression of randomised controlled trials reporting an association doi:10.1016/j.pcad.2018.05.004 between an intake of circa 25 g soya protein per day and blood 127. Jenkins DJA, Kendall CWC, Marchie A, et al. Direct comparison of a cholesterol. Atherosclerosis. 2008;200(1):13-27. dietary portfolio of cholesterol-lowering foods with a statin in doi:10.1016/j.atherosclerosis.2008.04.006 hypercholesterolemic participants. Am J Clin Nutr. 2005;81(2):380- 115. Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe Added to 387. Statin Therapy after Acute Coronary Syndromes. N Engl J Med. 128. Yokoyama Y, Nishimura K, Barnard ND, et al. Vegetarian Diets and 2015;372(25):2387-2397. doi:10.1056/NEJMoa1410489 Blood Pressure: A Meta-analysis. JAMA Intern Med. Published online 116. Sacks FM, Lichtenstein A, Van Horn L, et al. Soy protein, isoflavones, February 24, 2014. doi:10.1001/jamainternmed.2013.14547 and cardiovascular health: an American Heart Association Science 129. Dong J-Y, Tong X, Wu Z-W, Xun P-C, He K, Qin L-Q. Effect of soya Advisory for professionals from the Nutrition Committee. protein on blood pressure: a meta-analysis of randomised Circulation. 2006;113(7):1034-1044. controlled trials. Br J Nutr. 2011;106(3):317-326. doi:10.1161/CIRCULATIONAHA.106.171052 doi:10.1017/S0007114511000262

57 130. Taku K, Lin N, Cai D, et al. Effects of soy isoflavone extract 145. Bean Accounting: Are Soy-Based Food Products as Safe and Healthy supplements on blood pressure in adult humans: systematic review as Advertised? May 11, 2011 [Access date: May 29 2020]. Available and meta-analysis of randomized placebo-controlled trials. J from: https://www.scientificamerican.com/article/how-safe-is-soy/. Hypertens. 2010;28(10):1971-1982. doi:10.1097/HJH.0b013e32833c6edb 146. McCrory MA, Hamaker BR, Lovejoy JC, Eichelsdoerfer PE. Pulse Consumption, Satiety, and Weight Management. Adv Nutr. 131. Liu XX, Li SH, Chen JZ, et al. Effect of soy isoflavones on blood 2010;1(1):17-30. doi:10.3945/an.110.1006 pressure: a meta-analysis of randomized controlled trials. Nutr Metab Cardiovasc Dis. 2012;22(6):463-470. 147. FAO. Definition and classification of commodities: 4. Pulses and doi:10.1016/j.numecd.2010.09.006 derived products. Published 1994. www.fao.org/es/faodef/fdef04e.htm 132. Kou T, Wang Q, Cai J, et al. Effect of soybean protein on blood pressure in postmenopausal women: a meta-analysis of 148. Rebello CJ, Greenway FL, Finley JW. A review of the nutritional value randomized controlled trials. Food Funct. 2017;8(8):2663-2671. of legumes and their effects on obesity and its related co- doi:10.1039/c6fo01845a morbidities. Obesity reviews 2014;15(5):392-407. doi:10.1111/obr.12144

133. Stamler R. Implications of the INTERSALT study. Hypertension. 149. Messina MJ. Legumes and soybeans: overview of their nutritional 1991;17(1 Suppl):I16-20. doi:10.1161/01.hyp.17.1_suppl.i16 profiles and health effects. Am J Clin Nutr. 1999;70(3 Suppl):439S- 450S. 134. Helferich WG, Andrade JE, Hoagland MS. and breast cancer: a complex story. Inflammopharmacology. 2008;16(5):219- 150. Eckel RH, Jakicic JM, Ard JD, et al. 2013 AHA/ACC guideline on 226. doi:10.1007/s10787-008-8020-0 lifestyle management to reduce cardiovascular risk: A report of the American college of cardiology/American heart association task 135. Ju YH, Fultz J, Allred KF, Doerge DR, Helferich WG. Effects of dietary force on practice guidelines. J Am Coll Cardiol. 2014;63(25 PART and its metabolite, , at physiological concentrations B):2960-2984. doi:10.1016/j.jacc.2013.11.003 on the growth of estrogen-dependent human breast cancer (MCF- 7) tumors implanted in ovariectomized athymic mice. 151. Lichtenstein AH, Lichtenstein AH, Appel LJ, et al. Diet and Lifestyle Carcinogenesis. 2006;27(4):856-863. doi:10.1093/carcin/bgi320 Recommendations Revision 2006: A Scientific Statement From the American Heart Association Nutrition Committee. Circulation. 136. Ju YH, Doerge DR, Allred KF, Allred CD, Helferich WG. Dietary 2006;114(1):82-96. doi:10.1161/CIRCULATIONAHA.106.176158 negates the inhibitory effect of tamoxifen on growth of estrogen-dependent human breast cancer (MCF-7) cells implanted 152. Canadian Diabetes Association Clinical Practice Guidelines Expert in athymic mice. Cancer Res. 2002;62(9):2474-2477. Committee. Canadian Diabetes Association 2013 Clinical Practice Guidelines for the Prevention and Management of Diabetes in 137. Ju YH, Doerge DR, Woodling KA, Hartman JA, Kwak J, Helferich WG. Canada. Can J Diabetes. 2013;37(Suppl 1):S1-S212. Dietary genistein negates the inhibitory effect of letrozole on the growth of aromatase-expressing estrogen-dependent human 153. Becerra-Tomás N, Papandreou C, Salas-Salvadó J. Legume breast cancer cells (MCF-7Ca) in vivo. Carcinogenesis. Consumption and Cardiometabolic Health. Adv Nutr. 2019;10:S437- 2008;29(11):2162-2168. doi:10.1093/carcin/bgn161 S450. doi:10.1093/advances/nmz003

138. Wei Y, Lv J, Guo Y, et al. Soy intake and breast cancer risk: a 154. Viguiliouk E, Glenn AJ, Nishi SK, et al. Associations between Dietary prospective study of 300,000 Chinese women and a dose-response Pulses Alone or with Other Legumes and Cardiometabolic Disease meta-analysis. Eur J Epidemiol. Published online November 21, 2019. Outcomes: An Umbrella Review and Updated Systematic Review doi:10.1007/s10654-019-00585-4 and Meta-analysis of Prospective Cohort Studies. Adv Nutr.. 2019;10:S308-S319. doi:10.1093/advances/nmz113 139. Zhao T-T, Jin F, Li J-G, et al. Dietary isoflavones or isoflavone-rich food intake and breast cancer risk: A meta-analysis of prospective 155. Rautiainen S, Wang L, Lee I-M, Manson JE, Buring JE, Sesso HD. cohort studies. Clin Nutr. 2019;38(1):136-145. Higher Intake of Fruit, but Not Vegetables or Fiber, at Baseline Is doi:10.1016/j.clnu.2017.12.006 Associated with Lower Risk of Becoming Overweight or Obese in Middle-Aged and Older Women of Normal BMI at Baseline. J Nutr. 140. Applegate CC, Rowles JL, Ranard KM, Jeon S, Erdman JW. Soy 2015;145(5):960-968. doi:10.3945/jn.114.199158 Consumption and the Risk of Prostate Cancer: An Updated Systematic Review and Meta-Analysis. Nutrients. 2018;10(1). 156. Kim SJ, de Souza RJ, Choo VL, et al. Effects of dietary pulse doi:10.3390/nu10010040 consumption on body weight: a systematic review and meta- analysis of randomized controlled trials. Am J Clin Nutr. 141. Sak K. Current epidemiological knowledge about the role of 2016;103(5):1213-1223. doi:10.3945/ajcn.115.124677 flavonoids in prostate carcinogenesis. Exp Oncol. 2017;39(2):98-105. 157. Willett W, Rockström J, Loken B, et al. Food in the Anthropocene: 142. Zhang M, Wang K, Chen L, Yin B, Song Y. Is intake the EAT–Lancet Commission on healthy diets from sustainable food associated with decreased risk of prostate cancer? A systematic systems. The Lancet. 2019;393(10170):447-492. doi:10.1016/S0140- review of epidemiological studies based on 17,546 cases. 6736(18)31788-4 Andrology. 2016;4(4):745-756. doi:10.1111/andr.12196 158. wgflyer.pdf. Accessed June 12, 2020. 143. Fraanje WG, T. Soy: food, feed, and land use change 2020 [Access https://www.cerealsgrains.org/initiatives/definitions/Documents/W date: May 29 2020]. Available from: holeGrains/wgflyer.pdf https://foodsource.org.uk/sites/default/files/building- blocks/pdfs/fcrn_building_block_- 159. van der Kamp - 2013 - Whole Grain Definition New Perspectives for _soy_food_feed_and_land_use_change.pdf. Inclu.pdf. Accessed June 12, 2020. https://www.cerealsgrains.org/publications/plexus/cfwplexus/libra 144. Bøhn T, Cuhra M, Traavik T, Sanden M, Fagan J, Primicerio R. ry/books/Documents/WholeGrainsSummit2012/CPLEX-2013-1001- Compositional differences in soybeans on the market: glyphosate 08B.pdf accumulates in Roundup Ready GM soybeans. Food Chem. 2014;153:207-215. doi:10.1016/j.foodchem.2013.12.054 160. MARAGKOUDAKIS P. Whole Grain. EU Science Hub - European Commission. Published June 20, 2017. Accessed June 12, 2020.

58 https://ec.europa.eu/jrc/en/health-knowledge- cardiovascular risk factors: a randomized controlled trial. Diabetes gateway/promotion-prevention/nutrition/whole-grain Care. 2014;37(7):1806-1814. doi:10.2337/dc13-2990

161. Hollænder PLB, Ross AB, Kristensen M. Whole-grain and blood lipid 175. Vuksan V, Jenkins AL, Jenkins DJA, Rogovik AL, Sievenpiper JL, changes in apparently healthy adults: a systematic review and meta- Jovanovski E. Using cereal to increase intake to the analysis of randomized controlled studies. Am J Clin Nutr. recommended level and the effect of fiber on bowel function in 2015;102(3):556-572. doi:10.3945/ajcn.115.109165 healthy persons consuming North American diets. Am J Clin Nutr. 2008;88(5):1256-1262. doi:10.3945/ajcn.2008.25956 162. 97-1598.pdf. Accessed June 12, 2020. https://www.govinfo.gov/content/pkg/FR-1997-01-23/pdf/97- 176. Tang G, Wang D, Long J, Yang F, Si L. Meta-analysis of the 1598.pdf association between whole grain intake and coronary heart disease risk. Am J Cardiol. 2015;115(5):625-629. 163. Federal Register, Volume 71 Issue 98 (Monday, May 22, 2006). doi:10.1016/j.amjcard.2014.12.015 Accessed June 12, 2020. https://www.govinfo.gov/content/pkg/FR- 2006-05-22/html/06-4703.htm 177. Threapleton DE, Greenwood DC, Evans CEL, et al. Dietary fibre intake and risk of cardiovascular disease: systematic review and meta- 164. Canada H. Oat Products and Blood Cholesterol Lowering. aem. analysis. BMJ. 2013;347:f6879. doi:10.1136/bmj.f6879 Published November 25, 2010. Accessed June 9, 2020. https://www.canada.ca/en/health-canada/services/food- 178. Salas-Salvadó J, Bulló M, Babio N, et al. Reduction in the incidence nutrition/food-labelling/health-claims/assessments/products- of type 2 diabetes with the Mediterranean diet: results of the blood-cholesterol-lowering-summary-assessment-health-claim- PREDIMED-Reus nutrition intervention randomized trial. Diabetes about-products-blood-cholesterol-lowering.html Care. 2011;34(1):14-19. doi:10.2337/dc10-1288

165. Canada H. List of Dietary Fibres Reviewed and Accepted by Health 179. Salas-Salvadó J, Bulló M, Babio N, et al. Erratum. Reduction in the Canada’s Food Directorate. aem. Published June 23, 2017. Accessed Incidence of Type 2 Diabetes With the Mediterranean Diet: Results June 9, 2020. https://www.canada.ca/en/health- of the PREDIMED-Reus nutrition intervention randomized trial. canada/services/publications/food-nutrition/list-reviewed- Diabetes Care 2011;34:14–19. Diabetes Care. 2018;41(10):2259-2260. accepted-dietary-fibres.html doi:10.2337/dc18-er10

166. Scientific Opinion on the substantiation of a health claim related to 180. Chiavaroli L, Viguiliouk E, Nishi SK, et al. DASH Dietary Pattern and oat beta glucan and lowering blood cholesterol and reduced risk of Cardiometabolic Outcomes: An Umbrella Review of Systematic (coronary) heart disease pursuant to Article 14 of Regulation (EC) No Reviews and Meta-Analyses. Nutrients. 2019;11(2). 1924/2006. EFSA Journal. 2010;8(12):1885. doi:10.2903/j.efsa.2010.1885 doi:10.3390/nu11020338

167. Ho HVT, Sievenpiper JL, Zurbau A, et al. A systematic review and 181. Viguiliouk E, Kendall CW, Kahleová H, et al. Effect of vegetarian meta-analysis of randomized controlled trials of the effect of barley dietary patterns on cardiometabolic risk factors in diabetes: A β-glucan on LDL-C, non-HDL-C and apoB for cardiovascular disease systematic review and meta-analysis of randomized controlled risk reductioni-iv. Eur J Clin Nutr. 2016;70(11):1239-1245. trials. Clin Nutr. Published online June 13, 2018. doi:10.1038/ejcn.2016.89 doi:10.1016/j.clnu.2018.05.032

168. Ho HVT, Sievenpiper JL, Zurbau A, et al. The effect of oat β-glucan 182. Andrea J Glenn, Effie Viguiliouk, Maxine Seider, Sonia Blanco Mejia, on LDL-cholesterol, non-HDL-cholesterol and apoB for CVD risk Beatrice Boucher, Tauseef A. Khan, David JA Jenkins, Hana Kahleova, reduction: a systematic review and meta-analysis of randomised- Dario Rahelić, Jordi Salas-Salvadó, Cyril WC Kendall, John L controlled trials. Br J Nutr. 2016;116(8):1369-1382. Sievenpiper. Relation of vegetarian dietary patterns with major doi:10.1017/S000711451600341X cardiovascular outcomes: a systematic review and meta-analysis of prospective cohort studies. Front Nutr. Published online 2019. 169. Tiwari U, Cummins E. Meta-analysis of the effect of β-glucan intake on blood cholesterol and glucose levels. Nutrition. 2011;27(10):1008- 183. Becerra-Tomás N, Blanco Mejía S, Viguiliouk E, et al. Mediterranean 1016. doi:10.1016/j.nut.2010.11.006 diet, cardiovascular disease and mortality in diabetes: A systematic review and meta-analysis of prospective cohort studies and 170. Jovanovski E, Khayyat R, Zurbau A, et al. Should Viscous Fiber randomized clinical trials. Crit Rev Food Sci Nutr. 2020;60(7):1207- Supplements Be Considered in Diabetes Control? Results From a 1227. doi:10.1080/10408398.2019.1565281 Systematic Review and Meta-analysis of Randomized Controlled Trials. Diabetes Care. 2019;42(5):755-766. doi:10.2337/dc18-1126 184. Montagnese C, Santarpia L, Buonifacio M, et al. European food- based dietary guidelines: a comparison and update. Nutrition. 171. Bao L, Cai X, Xu M, Li Y. Effect of oat intake on glycaemic control and 2015;31(7-8):908-915. doi:10.1016/j.nut.2015.01.002 insulin sensitivity: a meta-analysis of randomised controlled trials. Br J Nutr. 2014;112(3):457-466. doi:10.1017/S0007114514000889 185. Montagnese C, Santarpia L, Iavarone F, et al. Food-Based Dietary Guidelines around the World: Eastern Mediterranean and Middle 172. Jenkins DJA, Kendall CWC, Augustin LSA, et al. Effect of wheat bran Eastern Countries. Nutrients. 2019;11(6). doi:10.3390/nu11061325 on glycemic control and risk factors for cardiovascular disease in type 2 diabetes. Diabetes Care. 2002;25(9):1522-1528. 186. Government of Canada. Canada’s dietary guidelines for health doi:10.2337/diacare.25.9.1522 professionals and policy makers. Available at https://food- guide.canada.ca/static/assets/pdf/CDG-EN-2018.pdf. 173. Vuksan V, Jenkins DJ, Spadafora P, et al. Konjac-mannan (glucomannan) improves glycemia and other associated risk factors 187. NHS. Eat well guide. Available at https://www.nhs.uk/live-well/eat- for coronary heart disease in type 2 diabetes. A randomized well/the-eatwell-guide/. controlled metabolic trial. Diabetes Care. 1999;22(6):913-919. doi:10.2337/diacare.22.6.913 188. U.S. Department of Health and Human Services and U.S. Department of Agriculture. 2015-2020 Dietary Guidelines for Americans. :144. 174. Jenkins DJA, Kendall CWC, Vuksan V, et al. Effect of lowering the glycemic load with canola oil on glycemic control and 189. Liu RH. Health-promoting components of fruits and vegetables in the diet. Adv Nutr. 2013;4(3):384S-92S. doi:10.3945/an.112.003517

59 190. Choo VL, Viguiliouk E, Blanco Mejia S, et al. Food sources of Sources of Sugars and Incident Metabolic Syndrome: A Systematic fructose-containing sugars and glycaemic control: systematic Review and Dose-Response Meta-Analysis of Prospective Cohort review and meta-analysis of controlled intervention studies. BMJ. Studies. JAMA Netw Open, in press. 2018;363:k4644. doi:10.1136/bmj.k4644 207. Liu Qi, Ayoub‐Charette Sabrina, Khan Tauseef Ahmad, et al. 191. Huang H, Chen G, Liao D, Zhu Y, Xue X. Effects of Berries Important Food Sources of Fructose‐Containing Sugars and Incident Consumption on Cardiovascular Risk Factors: A Meta-analysis with Hypertension: A Systematic Review and Dose‐Response Meta‐ Trial Sequential Analysis of Randomized Controlled Trials. Sci Rep. Analysis of Prospective Cohort Studies. J Am Heart Assoc. 2016;6:23625. doi:10.1038/srep23625 2019;8(24):e010977. doi:10.1161/JAHA.118.010977

192. Shin JY, Kim JY, Kang HT, Han KH, Shim JY. Effect of fruits and 208. Jenkins DJA, Srichaikul K, Kendall CWC, et al. The relation of low vegetables on metabolic syndrome: a systematic review and meta- glycaemic index fruit consumption to glycaemic control and risk analysis of randomized controlled trials. Int J Food Sci Nutr. factors for coronary heart disease in type 2 diabetes. Diabetologia. 2015;66(4):416-425. doi:10.3109/09637486.2015.1025716 2011;54(2):271-279. doi:10.1007/s00125-010-1927-1

193. Petersen KS, Clifton PM, Blanch N, Keogh JB. Effect of improving 209. Canada H. Plant Sterols and Blood Cholesterol Lowering. aem. dietary quality on carotid intima media thickness in subjects with Published May 26, 2010. Accessed June 9, 2020. type 1 and type 2 diabetes: a 12-mo randomized controlled trial. Am https://www.canada.ca/en/health-canada/services/food- J Clin Nutr. 2015;102(4):771-779. doi:10.3945/ajcn.115.112151 nutrition/food-labelling/health-claims/assessments/plant-sterols- blood-cholesterol-lowering-nutrition-health-claims-food- 194. Tsilas CS, de Souza RJ, Mejia SB, et al. Relation of total sugars, labelling.html fructose and sucrose with incident type 2 diabetes: a systematic review and meta-analysis of prospective cohort studies. CMAJ. 210. Canada H. Summary of Health Canada’s Assessment of a Health 2017;189(20):E711-E720. doi:10.1503/cmaj.160706 Claim about Soy Protein and Cholesterol Lowering. aem. Published March 7, 2015. Accessed June 9, 2020. 195. Zurbau A, Au-Yeung F, Blanco Mejia S, Khan TA, Vuksan V, https://www.canada.ca/en/health-canada/services/food- Jovanovski E, Leiter LA, Kendall CWC, Jenkins DJA, Sievenpiper JL*. nutrition/food-labelling/health-claims/assessments/summary- Relation of Different Fruit and Vegetable Sources with Incident assessment-health-claim-about-protein-cholesterol-lowering.html Cardiovascular Outcomes: A Systematic Review and Meta-Analysis of Prospective Cohort Studies. J Am Heart Assoc, in press. 211. Nutrition C for FS and A. Labeling & Nutrition - Qualified Health Claims: Letter of Enforcement Discretion - Nuts and Coronary Heart 196. Wang X, Ouyang Y, Liu J, et al. Fruit and vegetable consumption and Disease (Docket No 02P-0505). Accessed June 9, 2020. mortality from all causes, cardiovascular disease, and cancer: http://wayback.archive- systematic review and dose-response meta-analysis of prospective it.org/7993/20171114183724/https:/www.fda.gov/Food/IngredientsP cohort studies. BMJ. 2014;349:g4490. doi:10.1136/bmj.g4490 ackagingLabeling/LabelingNutrition/ucm072926.htm

197. Babio N, Toledo E, Estruch R, et al. Mediterranean diets and 212. Scientific Opinion on the substantiation of a health claim related to 3 metabolic syndrome status in the PREDIMED randomized trial. CMAJ. g/day plant sterols/stanols and lowering blood LDL-cholesterol and 2014;186(17):E649-657. doi:10.1503/cmaj.140764 reduced risk of (coronary) heart disease pursuant to Article 19 of Regulation (EC) No 1924/2006. EFSA Journal. 2012;10(5):2693. 198. Lustig RH. Fructose: it’s “alcohol without the buzz.” Adv Nutr. doi:10.2903/j.efsa.2012.2693 2013;4(2):226-235. doi:10.3945/an.112.002998 213. Jenkins DJA, Chiavaroli L, Wong JMW, et al. Adding 199. Lustig RH, Schmidt LA, Brindis CD. Public health: The toxic truth monounsaturated fatty acids to a dietary portfolio of cholesterol- about sugar. Nature. 2012;482(7383):27-29. doi:10.1038/482027a lowering foods in hypercholesterolemia. CMAJ. 2010;182(18):1961- 200. Zurger A. A Diet Manifesto: Drop the Apple and Walk Away. The 1967. doi:10.1503/cmaj.092128 New York Times. 2010 December 27, 2010;Sect. Health. 214. Low-density lipoproteins cause atherosclerotic cardiovascular 201. International Diabetes Federation. IDF Framework for Action on disease: pathophysiological, genetic, and therapeutic insights: a Sugar 2015 [Available from: consensus statement from the European Atherosclerosis Society https://www.idf.org/images/site1/content/Framework-for-Action- Consensus Panel | European Heart Journal | Oxford Academic. on-Sugar-010615.pdf. Accessed June 11, 2020. https://academic.oup.com/eurheartj/advance- 202. World Health Organization. Guideline: Sugars intake for adults and article/doi/10.1093/eurheartj/ehz962/5735221 children. Geneva; 2015. 215. Ference BA, Ginsberg HN, Graham I, et al. Low-density lipoproteins 203. Bays H, Weiter K, Anderson J. A randomized study of raisins versus cause atherosclerotic cardiovascular disease. 1. Evidence from alternative snacks on glycemic control and other cardiovascular risk genetic, epidemiologic, and clinical studies. A consensus statement factors in patients with type 2 diabetes mellitus. Phys Sportsmed. from the European Atherosclerosis Society Consensus Panel. Eur 2015;43(1):37-43. doi:10.1080/00913847.2015.998410 Heart J. 2017;38(32):2459-2472. doi:10.1093/eurheartj/ehx144

204. Kanellos PT, Kaliora AC, Tentolouris NK, et al. A pilot, randomized 216. Arnett DK, Blumenthal RS, Albert MA, et al. 2019 ACC/AHA Guideline controlled trial to examine the health outcomes of raisin on the Primary Prevention of Cardiovascular Disease: A Report of consumption in patients with diabetes. Nutrition. 2014;30(3):358-364. the American College of Cardiology/American Heart Association doi:10.1016/j.nut.2013.07.020 Task Force on Clinical Practice Guidelines. Circulation. 2019;140(11):e596-e646. doi:10.1161/CIR.0000000000000678 205. Anderson JW, Weiter KM, Christian AL, Ritchey MB, Bays HE. Raisins compared with other snack effects on glycemia and blood 217. Ference BA, Cannon CP, Landmesser U, Lüscher TF, Catapano AL, pressure: a randomized, controlled trial. Postgrad Med. Ray KK. Reduction of low density lipoprotein-cholesterol and 2014;126(1):37-43. doi:10.3810/pgm.2014.01.2723 cardiovascular events with proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors and statins: an analysis of FOURIER, SPIRE, 206. Semnani-Azad Z, Khan TA, Blanco Mejia S, de Souza R, Wolever and the Cholesterol Treatment Trialists Collaboration. Eur Heart J. TMS, Leiter LA, Kendall CWC, Hanley AJ, Sievenpiper JL. Food 2018;39(27):2540-2545. doi:10.1093/eurheartj/ehx450

60 218. Ference BA, Majeed F, Penumetcha R, Flack JM, Brook RD. Effect of 234. CardRehabMod6_HealthEating_FINAL.pdf. Accessed June 11, 2020. naturally random allocation to lower low-density lipoprotein https://www.heartfoundation.org.au/getmedia/7d0cdb2c-6884- cholesterol on the risk of coronary heart disease mediated by 4912-9bf0-00cb207c71f1/CardRehabMod6_HealthEating_FINAL.pdf polymorphisms in NPC1L1, HMGCR, or both: a 2 × 2 factorial Mendelian randomization study. J Am Coll Cardiol. 2015;65(15):1552- 235. Grundy Scott M., Stone Neil J., Bailey Alison L., et al. 2018 1561. doi:10.1016/j.jacc.2015.02.020 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/P CNA Guideline on the Management of Blood Cholesterol: A Report 219. Emerging Risk Factors Collaboration, Di Angelantonio E, Gao P, et al. of the American College of Cardiology/American Heart Association Lipid-related markers and cardiovascular disease prediction. JAMA. Task Force on Clinical Practice Guidelines. Circulation. 2012;307(23):2499-2506. doi:10.1001/jama.2012.6571 2019;139(25):e1082-e1143. doi:10.1161/CIR.0000000000000625

220. Ho HVT, Jovanovski E, Zurbau A, et al. A systematic review and 236. Stroes ES, Thompson PD, Corsini A, et al. Statin-associated muscle meta-analysis of randomized controlled trials of the effect of konjac symptoms: impact on statin therapy-European Atherosclerosis glucomannan, a viscous soluble fiber, on LDL cholesterol and the Society Consensus Panel Statement on Assessment, Aetiology and new lipid targets non-HDL cholesterol and apolipoprotein B. Am J Management. Eur Heart J. 2015;36(17):1012-1022. Clin Nutr. 2017;105(5):1239-1247. doi:10.3945/ajcn.116.142158 doi:10.1093/eurheartj/ehv043

221. Brown L, Rosner B, Willett WW, Sacks FM. Cholesterol-lowering 237. Catapano AL, Graham I, De Backer G, et al. 2016 ESC/EAS Guidelines effects of dietary fiber: a meta-analysis. Am J Clin Nutr. 1999;69(1):30- for the Management of Dyslipidaemias. Rev Esp Cardiol (Engl Ed). 42. doi:10.1093/ajcn/69.1.30 2017;70(2):115. doi:10.1016/j.rec.2017.01.002

222. Jenkins David J. A., Blanco Mejia Sonia, Chiavaroli Laura, et al. 238. The Portfolio Diet for Cardiovascular Disease Risk Reduction - 1st Cumulative Meta‐Analysis of the Soy Effect Over Time. J Am Heart Edition. Accessed June 11, 2020. Assoc 2019;8(13):e012458. doi:10.1161/JAHA.119.012458 https://www.elsevier.com/books/the-portfolio-diet-for- cardiovascular-disease-risk-reduction/jenkins/978-0-12-810510-8 223. Li SS, Blanco Mejia S, Lytvyn L, et al. Effect of Plant Protein on Blood Lipids: A Systematic Review and Meta-Analysis of Randomized 239. Serra-Majem L, Medina FX. The Mediterranean Diet as an Intangible Controlled Trials. J Am Heart Assoc. 2017;6(12). and Sustainable Food Culture. In: The Mediterranean Diet: An doi:10.1161/JAHA.117.006659 Evidence-Based Approach. ; 2015:37-46. doi:10.1016/B978-0-12- 407849-9.00004-X 224. Ha V, Sievenpiper JL, de Souza RJ, et al. Effect of dietary pulse intake on established therapeutic lipid targets for cardiovascular risk 240. D’Alessandro A, De Pergola G. Mediterranean Diet and reduction: a systematic review and meta-analysis of randomized Cardiovascular Disease: A Critical Evaluation of A Priori Dietary controlled trials. CMAJ. 2014;186(8):E252-262. doi:10.1503/cmaj.131727 Indexes. Nutrients. 2015;7(9):7863-7888. doi:10.3390/nu7095367

225. Law M. Plant sterol and stanol margarines and health. BMJ. 241. Dernini S, Berry EM. Mediterranean Diet: From a Healthy Diet to a 2000;320(7238):861-864. Sustainable Dietary Pattern. Frontiers in Nutrition. 2015;2. doi:10.3389/fnut.2015.00015 226. Abumweis SS, Barake R, Jones PJH. Plant sterols/stanols as cholesterol lowering agents: A meta-analysis of randomized 242. Grosso G. The Mediterranean diet as a sustainable dietetic model. controlled trials. Food Nutr Res. 2008;52. doi:10.3402/fnr.v52i0.1811 European Journal of Public Health. 2018;28(suppl_4). doi:10.1093/eurpub/cky213.765 227. Ras RT, Geleijnse JM, Trautwein EA. LDL-cholesterol-lowering effect of plant sterols and stanols across different dose ranges: a meta- 243. UNESCO. Representive List of the Intangible Cultural Heritage of analysis of randomised controlled studies. Br J Nutr. 2014;112(2):214- Humanity. Published 2010. 219. doi:10.1017/S0007114514000750 http://www.unesco.org/culture/ich/en/RL/00394

228. Musa-Veloso K, Paulionis L, Poon T, Lee HY. The effects of 244. Agriculture USD of H and HS and USD of. 2015–2020 Dietary consumption on fasting blood lipid levels: a systematic review and Guidelines for Americans. 8th Edition. meta-analysis of randomised controlled trials. J Nutr Sci. 2016;5. doi:10.1017/jns.2016.19 245. Da Silva R, Bach-Faig A, Raidó Quintana B, Buckland G, Vaz De Almeida MD, Serra-Majem L. Worldwide variation of adherence to 229. Liu K, Hui S, Wang B, Kaliannan K, Guo X, Liang L. Comparative the Mediterranean diet, in 1961-1965 and 2000-2003. Pub Health effects of different types of tree nut consumption on blood lipids: a Nutri 2009;12(9 SPEC. ISSUE 9A):1676-1684. network meta-analysis of clinical trials. Am J Clin Nutr. 2020;111(1):219- doi:10.1017/S1368980009990541 227. doi:10.1093/ajcn/nqz280 246. Achour N, El Ati J, Traissac P, et al. Nutrition transition among 230. Li Y-H, Ueng K-C, Jeng J-S, et al. 2017 Taiwan lipid guidelines for high adolescents of a south-Mediterranean country: Dietary patterns, risk patients. Journal of the Formosan Medical Association. association with socio-economic factors, overweight and blood 2017;116(4):217-248. doi:10.1016/j.jfma.2016.11.013 pressure. A cross-sectional study in Tunisia. Nutr J. 2011;10(38).

231. Anderson TJ, Grégoire J, Pearson GJ, et al. 2016 Canadian 247. León-Muñoz LM, Guallar-Castillón P, Graciani A, et al. Adherence to Cardiovascular Society Guidelines for the Management of the Mediterranean Diet Pattern Has Declined in Spanish Adults. TJ Dyslipidemia for the Prevention of Cardiovascular Disease in the Nutr. 2012;142(10):1843-1850. doi:10.3945/jn.112.164616 Adult. Can J Cardiol. 2016;32(11):1263-1282. doi:10.1016/j.cjca.2016.07.510 248. Bonaccio M, Di Castelnuovo A, Bonanni A, et al. Decline of the Mediterranean diet at a time of economic crisis. Results from the 232. Nutrition Therapy - Canadian Journal of Diabetes. Accessed June 11, Moli-sani study. Nutr Metab Cardiovas. 2014;24(8):853-860. 2020. https://www.canadianjournalofdiabetes.com/article/S1499- doi:10.1016/j.numecd.2014.02.014 2671(17)30819-5/fulltext 249. Keys A, Mienotti A, Karvonen MJ, et al. The diet and 15-year death 233. BDA. Cholesterol. Accessed June 11, 2020. rate in the seven countries study. Am J Epidemiol. 1986;124(6):903- https://www.bda.uk.com/resource/cholesterol.html 915. doi:10.1093/oxfordjournals.aje.a114480

61 250. Garcia M, Bihuniak JD, Shook J, Kenny A, Kerstetter J, Huedo-Medina Diffusion? J Cardiol Therapy. 2015;2(6):452-455. TB. The Effect of the Traditional Mediterranean-Style Diet on doi:10.17554/j.issn.2309-6861.2015.02.99 Metabolic Risk Factors: A Meta-Analysis. Nutrients. 2016;8(3):168. doi:10.3390/nu8030168 265. Alberti KGMM, Zimmet P, Shaw J. Metabolic syndrome - A new world-wide definition. A consensus statement from the International 251. Schwingshackl L, Hoffmann G. Mediterranean dietary pattern, Diabetes Federation. Diabetic Medicine. 2006;23(5):469-480. inflammation and endothelial function: A systematic review and doi:10.1111/j.1464-5491.2006.01858.x meta-analysis of intervention trials. Nutr Metab Cardiovas. 2014;24(9):929-939. doi:10.1016/j.numecd.2014.03.003 266. Abenavoli L. Non-alcoholic fatty liver disease and beneficial effects of dietary supplements. World J Hepatol. 2015;7(12):1723-1724. 252. Esposito K, Kastorini C-M, Panagiotakos DB, Giugliano D. doi:10.4254/wjh.v7.i12.1723 Mediterranean Diet and Weight Loss: Meta-Analysis of Randomized Controlled Trials. Metabolic Syndrome and Related Disorders. 267. Anania C, Massimo Perla F, Olivero F, Pacifico L, Chiesa C. 2011;9(1):1-12. doi:10.1089/met.2010.0031 Mediterranean diet and nonalcoholic fatty liver disease. World J Gastroenterol. 2018;24(19):2083-2094. doi:10.3748/wjg.v24.i19.2083 253. Shai I, Schwarzfuchs D, Henkin Y, et al. Weight loss with a low- carbohydrate, Mediterranean, or low-fat diet. N Engl J Med. 268. Schwingshackl L, Morze J, Hoffmann G. Mediterranean diet and 2008;359(3):229-241. doi:10.1056/NEJMoa0708681 health status: Active ingredients and pharmacological mechanisms. Br. J. Pharmacol. 2020;177(6):1241-1257. doi:10.1111/bph.14778 254. Salas-Salvadó J, Díaz-López A, Ruiz-Canela M, et al. Effect of a Lifestyle Intervention Program With Energy-Restricted 269. Anastasiou CA, Yannakoulia M, Kosmidis MH, et al. Mediterranean Mediterranean Diet and Exercise on Weight Loss and Cardiovascular diet and cognitive health: Initial results from the Hellenic Risk Factors: One-Year Results of the PREDIMED-Plus Trial. Diabetes Longitudinal Investigation of Ageing and Diet. PLoS ONE. 2017;12(8). Care. 2019;42(5):777-788. doi:10.2337/dc18-0836 doi:10.1371/journal.pone.0182048

255. Pan B, Wu Y, Yang Q, et al. The impact of major dietary patterns on 270. Shannon OM, Stephan BCM, Granic A, et al. Mediterranean diet glycemic control, cardiovascular risk factors, and weight loss in adherence and cognitive function in older UK adults: The European patients with type 2 diabetes: A network meta-analysis. J Evid Based Prospective Investigation into Cancer and Nutrition-Norfolk (EPIC- Med. 2019;12(1):29-39. doi:10.1111/jebm.12312 Norfolk) Study. Am J Clin Nutr. 2019;110(4):938-948. doi:10.1093/ajcn/nqz114 256. Chatzi L, Rifas-Shiman SL, Georgiou V, et al. Adherence to the Mediterranean diet during pregnancy and offspring adiposity and 271. Schwingshackl L, Schwedhelm C, Galbete C, Hoffmann G. cardiometabolic traits in childhood. Pediatric Obesity. 2017;12(Suppl Adherence to mediterranean diet and risk of cancer: An updated 1):47-56. doi:10.1111/ijpo.12191 systematic review and meta-analysis. Nutrients. 2017;9(10):1063. doi:10.3390/nu9101063 257. Salas-Salvadó J, Becerra-Tomás N, García-Gavilán JF, Bulló M, Barrubés L. Mediterranean Diet and Cardiovascular Disease 272. Romagnolo DF, Selmin OI. Mediterranean Diet and Prevention of Prevention: What do We Know? Progress in Cardiovascular Chronic Diseases. Nutrition Today. 2017;52(5):208-222. Diseases. 2018;0(0). doi:10.1016/j.pcad.2018.04.006 doi:10.1097/NT.0000000000000228

258. de Lorgeril M, Salen P, Martin JL, Monjaud I, Delaye J, Mamelle N. 273. Soltani S, Jayedi A, Shab-Bidar S, Becerra-Tomás N, Salas-Salvadó J. Mediterranean diet, traditional risk factors, and the rate of Adherence to the Mediterranean Diet in Relation to All-Cause cardiovascular complications after myocardial infarction: final report Mortality: A Systematic Review and Dose-Response Meta-Analysis of the Lyon Diet Heart Study. Circulation. 1999;99(6):779-785. of Prospective Cohort Studies. Advances in Nutrition. 2019;10(6):1029-1039. doi:10.1093/advances/nmz041 259. Singh RB, Dubnov G, Niaz MA, et al. Effect of an Indo-Mediterranean diet on progression of coronary artery disease in high risk patients 274. Ramezani-Jolfaie N, Mohammadi M, Salehi-Abargouei A. The effect (Indo-Mediterranean Diet Heart Study): a randomised single-blind of healthy Nordic diet on cardio-metabolic markers: a systematic trial. Lancet (London, England). 2002;360(9344):1455-1461. review and meta-analysis of randomized controlled clinical trials. Eur doi:10.1016/S0140-6736(02)11472-3 J Nutr. 2019;58(6):2159-2174. doi:10.1007/s00394-018-1804-0

260. Estruch R, Ros E, Salas-Salvadó J, et al. Primary Prevention of 275. Adamsson V, Reumark A, Fredriksson I-B, et al. Effects of a healthy Cardiovascular Disease with a Mediterranean Diet Supplemented Nordic diet on cardiovascular risk factors in hypercholesterolaemic with Extra-Virgin Olive Oil or Nuts. N Engl J Med. 2018;378(25):e34. subjects: a randomized controlled trial (NORDIET). J Intern Med. doi:10.1056/NEJMoa1800389 2011;269(2):150-159. doi:10.1111/j.1365-2796.2010.02290.x

261. Salas-Salvadó J, Guasch-Ferré M, Lee C-H, Estruch R, Clish CB, Ros E. 276. Poulsen SK, Due A, Jordy AB, et al. Health effect of the New Nordic Protective Effects of the Mediterranean Diet on Type 2 Diabetes and Diet in adults with increased waist circumference: a 6-mo Metabolic Syndrome. J Nutr 2016;146(4):920S. randomized controlled trial. Am J Clin Nutr. 2014;99(1):35-45. doi:10.3945/jn.115.218487 doi:10.3945/ajcn.113.069393

262. Benson G, Pereira RF, Boucher JL. Rationale for the use of a 277. Sakhaei R, Ramezani-Jolfaie N, Mohammadi M, Salehi-Abargouei A. mediterranean management. Diabetes Spectrum. The healthy Nordic dietary pattern has no effect on inflammatory 2011;24(1):36-40. doi:10.2337/diaspect.24.1.36 markers: A systematic review and meta-analysis of randomized controlled clinical trials. Nutrition. 2019;58:140-148. 263. Godos J, Zappalà G, Bernardini S, Giambini I, Bes-Rastrollo M, doi:10.1016/j.nut.2018.06.020 Martinez-Gonzalez M. Adherence to the Mediterranean diet is inversely associated with metabolic syndrome occurrence: a meta- 278. Kolehmainen M, Ulven SM, Paananen J, et al. Healthy Nordic diet analysis of observational studies. Int J Food Sci Nutr 2017;68(2):138- downregulates the expression of genes involved in inflammation in 148. doi:10.1080/09637486.2016.1221900 subcutaneous adipose tissue in individuals with features of the metabolic syndrome. Am J Clin Nutr. 2015;101(1):228-239. 264. Innocenti A, Giampietro C, Fusi J, Galetta F, Franzoni F, Giampietro doi:10.3945/ajcn.114.092783 O. Can Mediterranean Diet Counteract Metabolic Syndrome

62 279. Zimorovat A, Mohammadi M, Ramezani-Jolfaie N, Salehi-Abargouei 295. Micha R, Wallace SK, Mozaffarian D. Red and processed meat A. The healthy Nordic diet for blood glucose control: a systematic consumption and risk of incident coronary heart disease, stroke, review and meta-analysis of randomized controlled clinical trials. and diabetes: A systematic review and meta-analysis. Circulation. Acta Diabetol. 2020;57(1):1-12. doi:10.1007/s00592-019-01369-8 2010;121(21):2271-2283. doi:10.1161/CIRCULATIONAHA.109.924977

280. Ohlsson B, Höglund P, Roth B, Darwiche G. Modification of a 296. Yokoyama Y, Barnard ND, Levin SM, Watanabe M. Vegetarian diets traditional breakfast leads to increased satiety along with attenuated and glycemic control in diabetes: a systematic review and meta- plasma increments of glucose, C-peptide, insulin, and glucose- analysis. Cardiovasc Diagn Ther. 2014;4(5):373-382. dependent insulinotropic polypeptide in humans. Nutr Res. doi:10.3978/j.issn.2223-3652.2014.10.04 2016;36(4):359-368. doi:10.1016/j.nutres.2015.12.004 297. Barnard RJ, Jung T, Inkeles SB. Diet and exercise in the treatment of 281. Ohlsson B, Darwiche G, Roth B, Höglund P. Alignments of endocrine, NIDDM. The need for early emphasis. Diabetes Care. anthropometric, and metabolic parameters in type 2 diabetes after 1994;17(12):1469-1472. intervention with an Okinawa-based Nordic diet. Food Nutr Res. 2018;62. doi:10.29219/fnr.v62.1328 298. Olfert MD, Wattick RA. Vegetarian Diets and the Risk of Diabetes. Curr Diab Rep. 2018;18(11). doi:10.1007/s11892-018-1070-9 282. Poulsen SK, Crone C, Astrup A, Larsen TM. Long-term adherence to the New Nordic Diet and the effects on body weight, 299. Tonstad S, Butler T, Yan R, Fraser GE. Type of Vegetarian Diet, Body anthropometry and blood pressure: a 12-month follow-up study. Eur Weight, and Prevalence of Type 2 Diabetes. Diabetes Care. J Nutr. 2015;54(1):67-76. doi:10.1007/s00394-014-0686-z 2009;32(5):791-796. doi:10.2337/dc08-1886

283. Kanerva N, Kaartinen NE, Schwab U, Lahti-Koski M, Männistö S. 300. Rizzo NS, Sabaté J, Jaceldo-Siegl K, Fraser GE. Vegetarian dietary Adherence to the Baltic Sea diet consumed in the Nordic countries patterns are associated with a lower risk of metabolic syndrome: is associated with lower abdominal obesity. Br J Nutr. the adventist health study 2. Diabetes Care. 2011;34(5):1225-1227. 2013;109(3):520-528. doi:10.1017/S0007114512001262 doi:10.2337/dc10-1221

284. Roswall N, Sandin S, Scragg R, et al. No association between 301. Wang F, Zheng J, Yang B, Jiang J, Fu Y, Li D. Effects of Vegetarian adherence to the healthy Nordic food index and cardiovascular Diets on Blood Lipids: A Systematic Review and Meta-Analysis of disease amongst Swedish women: a cohort study. J Intern Med. Randomized Controlled Trials. J Am Heart Assoc. 2015;278(5):531-541. doi:10.1111/joim.12378 2015;4(10):e002408. doi:10.1161/JAHA.115.002408

285. Hansen CP, Overvad K, Kyrø C, et al. Adherence to a Healthy Nordic 302. Fontana L, Meyer TE, Klein S, Holloszy JO. Long-Term Low-Calorie Diet and Risk of Stroke: A Danish Cohort Study. Stroke. Low-Protein Vegan Diet and Endurance Exercise are Associated 2017;48(2):259-264. doi:10.1161/STROKEAHA.116.015019 with Low Cardiometabolic Risk. https://home.liebertpub.com/rej. doi:10.1089/rej.2006.0529 286. Galbete C, Kröger J, Jannasch F, et al. Nordic diet, Mediterranean diet, and the risk of chronic diseases: the EPIC-Potsdam study. BMC 303. van Nielen M, Feskens EJM, Rietman A, Siebelink E, Mensink M. Partly Med. 2018;16. doi:10.1186/s12916-018-1082-y replacing meat protein with soy protein alters insulin resistance and blood lipids in postmenopausal women with abdominal obesity. J 287. Lacoppidan SA, Kyrø C, Loft S, et al. Adherence to a Healthy Nordic Nutr. 2014;144(9):1423-1429. doi:10.3945/jn.114.193706 Food Index Is Associated with a Lower Risk of Type-2 Diabetes— The Danish Diet, Cancer and Health Cohort Study. Nutrients. 304. Lea EJ, Crawford D, Worsley A. Public views of the benefits and 2015;7(10):8633-8644. doi:10.3390/nu7105418 barriers to the consumption of a plant-based diet. Eur J Clin Nutr. 2006;60(7):828-837. doi:10.1038/sj.ejcn.1602387 288. Brader L, Uusitupa M, Dragsted LO, Hermansen K. Effects of an isocaloric healthy Nordic diet on ambulatory blood pressure in 305. Moore WJ, McGrievy ME, Turner-McGrievy GM. Dietary adherence metabolic syndrome: a randomized SYSDIET sub-study. Eur J Clin and acceptability of five different diets, including vegan and Nutr. 2014;68(1):57-63. doi:10.1038/ejcn.2013.192 vegetarian diets, for weight loss: The New DIETs study. Eating Behaviors. 2015;19:33-38. doi:10.1016/j.eatbeh.2015.06.011 289. Fattahi MR, Niknam R, Safarpour A, Sepehrimanesh M, Lotfi M. The Prevalence of Metabolic Syndrome In Non-alcoholic Fatty Liver 306. Dansinger ML, Gleason JA, Griffith JL, Selker HP, Schaefer EJ. Disease; A Population-Based Study. Middle East J Dig Dis. Comparison of the Atkins, Ornish, , and Zone Diets 2016;8(2):131-137. doi:10.15171/mejdd.2016.18 for Weight Loss and Heart Disease Risk Reduction: A Randomized Trial. JAMA. 2005;293(1):43-53. doi:10.1001/jama.293.1.43 290. Orlich MJ, Singh PN, Sabaté J, et al. Vegetarian dietary patterns and mortality in Adventist Health Study 2. JAMA Intern Med. 307. Spencer M, Kurzer A, Cienfuegos C, Guinard J-X. Student consumer 2013;173(13):1230-1238. doi:10.1001/jamainternmed.2013.6473 acceptance of plant-forward burrito bowls in which two-thirds of the meat has been replaced with legumes and vegetables: The 291. Appleby PN, Thorogood M, Mann JI, Key TJ. The Oxford Vegetarian Flexitarian FlipTM in university dining venues. Appetite. 2018;131:14-27. Study: an overview. Am J Clin Nutr. 1999;70(3 Suppl):525S-531S. doi:10.1016/j.appet.2018.08.030 doi:10.1093/ajcn/70.3.525s 308. Tomova A, et al. The Effects of Vegetarian and Vegan Diets on Gut 292. Kwok CS, Umar S, Myint PK, Mamas MA, Loke YK. Vegetarian diet, Microbiota. Front Nutr. 2019 Apr 17;6:47. doi: Seventh Day Adventists and risk of cardiovascular mortality: a 10.3389/fnut.2019.00047. eCollection 2019. systematic review and meta-analysis. Int J Cardiol. 2014;176(3):680- 686. doi:10.1016/j.ijcard.2014.07.080 309. Rinninella E, Cintoni M, Raoul P, Lopetuso LR, Scaldaferri F, Pulcini G, Miggiano GAD, Gasbarrini A, 293. Ornish D, Scherwitz LW, Billings JH, et al. Intensive lifestyle changes Mele MC.Rinninella E, et al. Food Components and Dietary Habits: for reversal of coronary heart disease. JAMA. 1998;280(23):2001- Keys for a Healthy Gut Microbiota Composition. Nutrients. 2019 Oct 2007. 7;11(10):2393. doi: 10.3390/nu11102393.

294. Spence JD, Tangney C. Lower risk of stroke with a vegetarian diet. 310. Muralidharan J, Galiè S, Hernández-Alonso P, Bulló M, Salas-Salvadó Neurology. 2020;94(11):463-464. J.Muralidharan J, et al. Plant-Based Fat, Dietary Patterns Rich in doi:10.1212/WNL.0000000000009092

63 Vegetable Fat and Gut Microbiota Modulation. Front Nutr. 2019 Oct 320. De Filippo C, Cavalieri D, Di Paola M, et al. Impact of diet in shaping 11;6:157. doi: 10.3389/fnut.2019.00157. eCollection 2019 gut microbiota revealed by a comparative study in children from Europe and rural Africa. Proc Natl Acad Sci USA. 2010;107(33):14691- 311. Wu GD, Chen J, Hoffmann C, et al. Linking long-term dietary patterns 14696. doi:10.1073/pnas.1005963107 with gut microbial enterotypes. Science. 2011;334(6052):105-108. doi:10.1126/science.1208344 321. Livsmedelsverket: Find your way to eat greener, not too much and be active; 2015. http://www.fao.org/3/a-az854e.pdf 312. Tan J, McKenzie C, Potamitis M, Thorburn AN, Mackay CR, Macia L. The role of short-chain fatty acids in health and disease. Adv 322. The Eatwell Guide. GOV.UK. Accessed June 11, 2020. Immunol. 2014;121:91-119. doi:10.1016/B978-0-12-800100-4.00003-9 https://www.gov.uk/government/publications/the-eatwell-guide

313. Canfora EE, Meex RCR, Venema K, Blaak EE. Gut microbial 323. Voeding. Vlaams Instituut Gezond Leven. Accessed June 11, 2020. metabolites in obesity, NAFLD and T2DM. Nature Reviews https://www.gezondleven.be/themas/voeding Endocrinology. Published online January 22, 2019:1. doi:10.1038/s41574-019-0156-z 324. Eating healthy with the Wheel of Five | Nutrition center. Accessed June 11, 2020. https://www.voedingscentrum.nl/nl/gezond-eten- 314. Reynés B, Palou M, Rodríguez AM, Palou A. Regulation of Adaptive met-de-schijf-van-vijf.aspx Thermogenesis and Browning by Prebiotics and Postbiotics. Front Physiol. 2019;9. doi:10.3389/fphys.2018.01908 328. https://www.dge.de/ernaehrungspraxis/vollwertige- ernaehrung/10-regeln-der-dge/ 315. Singh RK, Chang H-W, Yan D, et al. Influence of diet on the gut microbiome and implications for human health. J Transl Med. 329. Canada H. Welcome to Canada’s food guide. Published October 4, 2017;15. doi:10.1186/s12967-017-1175-y 2018. Accessed June 11, 2020. https://food-guide.canada.ca/en/, https://food-guide.canada.ca/ 316. Verdam FJ, Fuentes S, de Jonge C, et al. Human intestinal microbiota composition is associated with local and systemic inflammation in 330. Research FAB. FAB: Willett et al 2019 - Food in the Anthropocene: obesity: Obese Gut Microbiota and Inflammation. Obesity. the EAT–Lancet Commission on healthy diets from sustainable food 2013;21(12):E607-E615. doi:10.1002/oby.20466 systems. Accessed June 11, 2020. https://www.fabresearch.org/viewItem.php?id=12375 317. Koeth RA, Wang Z, Levison BS, et al. Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes 331. Springmann M, Spajic L, Clark MA et al. The healthiness and atherosclerosis. Nat Med. 2013;19(5):576-585. doi:10.1038/nm.3145 sustainability of national and global food based dietary guidelines: modelling study. BMJ 2020; 370:m2322. doi: 10.1136/bmj.m2322. 318. Sonnenburg JL, Bäckhed F. Diet-microbiota interactions as moderators of human metabolism. Nature. 2016;535(7610):56-64. doi:10.1038/nature18846

319. Jain A, Li XH, Chen WN. Similarities and differences in gut microbiome composition correlate with dietary patterns of Indian and Chinese adults. AMB Express. 2018;8. doi:10.1186/s13568-018- 0632-1

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