Suboptimal nutrition is a leading cause of poor health. Nutrition and policy science have advanced rapidly, creating confusion yet also providing powerful opportunities to reduce the adverse health and economic impacts of poor diets. This review considers the history, new evidence, controversies, and corresponding lessons for modern dietary and policy priorities for cardiovascular diseases, obesity, and diabetes mellitus. Major identified themes include the importance of evaluating the full diversity of diet-related risk pathways, not only blood lipids or obesity; focusing on foods and overall diet patterns, rather than single isolated nutrients; recognizing the complex influences of different foods on long-term weight regulation, rather than simply counting calories; and characterizing and implementing evidence-based strategies, including policy approaches, for lifestyle change. Evidence-informed dietary priorities include increased fruits, nonstarchy vegetables, nuts, legumes, fish, vegetable oils, yogurt, and minimally processed whole grains; and fewer red meats, processed (eg, sodium-preserved) meats, and foods rich in refined grains, starch, added sugars, salt, and trans fat. More investigation is needed on the cardiometabolic effects of phenolics, dairy fat, probiotics, fermentation, coffee, tea, cocoa, eggs, specific vegetable and tropical oils, vitamin D, individual fatty acids, and diet-microbiome interactions. Little evidence to date supports the cardiometabolic relevance of other popular priorities: eg, local, organic, grass-fed, farmed/wild, or non–genetically modified. Evidence-based personalized nutrition appears to depend more on nongenetic characteristics (eg, physical activity, abdominal adiposity, gender, socioeconomic status, culture) than genetic factors. Food choices must be strongly supported by clinical behavior change efforts, health systems reforms, novel technologies, and robust policy strategies targeting economic incentives, schools and workplaces, neighborhood environments, and the food system. Scientific advances provide crucial new insights on optimal targets and best practices to reduce the burdens of diet-related cardiometabolic diseases.

Introduction

Suboptimal diet is the leading risk factor for death and disability in the United States and worldwide.1,2 Among disadvantaged populations in all nations, hunger and malnutrition cause enormous suffering. Simultaneously, diet-related cardiometabolic diseases such as coronary heart disease (CHD), stroke, type 2 diabetes mellitus, and obesity produce even larger global health burdens. Other vascular conditions including peripheral arterial disease, chronic kidney disease, cognitive decline, heart failure, and atrial fibrillation are also influenced by diet-related risk factors. Worldwide, chronic diseases will cause $17.3 trillion of cumulative economic loss between 2011 and 2030 from healthcare expenditures, reduced productivity, and lost capital.3 Considering these health and economic burdens, diet-related illnesses are among the leading priorities of our time.

In recent years, global dietary patterns have shifted in nearly every nation in the world.4 At the same time, nutrition science has advanced remarkably. In comparison with historical dietary recommendations which were based largely on cross-national studies, short-term experiments, and animal models, nutrition science has been transformed in the past 2 decades by more rigorous evidence from well-designed metabolic studies, prospective cohorts, and randomized clinical trials.

Several key lessons have emerged (Table 1). First, it is now evident that dietary habits influence diverse cardiometabolic risk factors, including not only obesity and low-density lipoprotein (LDL) cholesterol, but also blood pressure (BP), glucose-insulin homeostasis, lipoprotein concentrations and function, oxidative stress, inflammation, endothelial health, hepatic function, adipocyte metabolism, cardiac function, metabolic expenditure, pathways of weight regulation, visceral adiposity, and the microbiome (Figure 1). Whereas decades of dietary recommendations focused on dietary fat and blood cholesterol and current dietary discussions are often preoccupied with total calories and obesity, the full health impact of diet extends far beyond these pathways. Cardiometabolic consequences of any nutrient, food, or overall diet should not be extrapolated from any single surrogate outcome,5 but assessed based on the totality of evidence including interventional trials evaluating multiple risk pathways, prospective cohort studies of clinical events, and, where available, randomized trials of clinical events.6,7

Table 1. Key New Lessons from Modern Nutritional Science Diverse physiological effects of diet Dietary habits influence a myriad of cardiometabolic risk factors, including blood pressure, glucose-insulin homeostasis, lipoprotein concentrations and function, inflammation, endothelial health, hepatic function, adipocyte metabolism, cardiac function, metabolic expenditure, and pathways of weight regulation, visceral adiposity, and the microbiome. Focus on single surrogate outcomes can be misleading. Based on these diverse effects, diet quality is more relevant than quantity, and the primary emphasis should be cardiovascular and metabolic health, not simply body weight or obesity. Importance of foods and diet patterns Specific foods and overall diet patterns, rather than single isolated nutrients, are most relevant for cardiometabolic health. The historical focus on isolated nutrients contributes to confusion about what constitutes a healthy diet, distracts from more effective strategies, and drives industry, policy makers, and the public toward diets which meet selected nutrient cut points but provide little health benefit. Complexity of obesity and weight regulation Diet quality influences diverse pathways related to weight homeostasis, including satiety, hunger, brain reward, glucose-insulin responses, hepatic de novo lipogenesis, adipocyte function, metabolic expenditure, and the microbiome. For long-term weight control, all calories are not created equal because of the divergent long-term effects of different foods on these pathways of weight homeostasis. Individual, health systems, and policy approaches for behavior change Multiple evidence-based strategies for improving dietary behaviors have now been identified, including at the individual (patient) level, in health systems, and in populations. Integrated, multicomponent approaches that include upstream policy measures, midstream educational efforts, and downstream community and environmental approaches may be especially effective.

Figure 1. Diet and cardiovascular and metabolic risk – pathways and mechanisms. Each of these dietary factors influences many or even all of these pathways, which could also be modified in some cases by underlying individual characteristics. Selected major effects are detailed in the text sections on each dietary factor.

A second key lesson is the importance of specific foods and overall diet patterns, rather than single isolated nutrients, for cardiometabolic risk.8,9 Indeed, focusing on isolated nutrients often leads to paradoxical dietary choices and industry formulations. A food-based approach also better facilitates public guidance and minimizes industry manipulation.

Third, the science of obesity has progressed dramatically. Similar to lessons for CHD risk, the primary prevention of obesity – avoidance of long-term weight gain – may prove more effective and enduring than secondary prevention – obesity treatment after it has occurred. The diverse, complex physiological mechanisms of long-term weight homeostasis are also being elucidated. These lines of evidence indicate that an energy-imbalance concept of obesity is oversimplified. Whereas short-term weight loss can be achieved by any type of calorie-reduced diet, in the long term, counting calories may not be biologically nor behaviorally relevant. Rather, the quality and types of foods consumed influence diverse pathways related to weight homeostasis, such as satiety, hunger, brain reward, glucose-insulin responses, hepatic de novo lipogenesis, adipocyte function, metabolic expenditure, and the microbiome. Thus, all calories are not equal for long-term adiposity: certain foods impair pathways of weight homeostasis, others have relatively neutral effects, and others promote the integrity of weight regulation.

Finally, major strides have been made in the science of individual, sociocultural, and environmental determinants of dietary choices. Influences are complex, including individual-level, sociocultural, community, agricultural, industry, governmental, and global contributors.10 Several individual, health system, and policy-level strategies now have strong evidence for efficacy.11 Elucidation of methods for better translation of these approaches is needed.

This article summarizes the modern evidence for health effects of diet on cardiometabolic diseases, including key evidence-based priorities, relevant mechanisms, and major unanswered questions, and the evidence on barriers and opportunities for behavior change in the clinic, health system, and population, including novel policy and technology strategies.

Nutrients, Foods, and Diet Patterns – a Historical Evolution

In 1747, Captain James Lind performed one of the earliest recorded clinical trials. Based on earlier observations, he assigned British sailors who had scurvy to several different treatments.9,12 Only 1 group – those receiving citrus fruits – improved, providing new evidence that a specific dietary factor could cure disease. By the turn of the century, the British fleet routinely added lemon or lime juice to rations, a practice making them famous as “limeys”.

Yet, it was not until 1932 that the first vitamin was isolated – vitamin C – and was verified as the active protective constituent against scurvy. This confirmed, for the first time, that specific dietary nutrients could prevent disease. Over the next 2 decades, an explosion of nutrition science confirmed other single-nutrient diseases such as beriberi (thiamine), pellagra (niacin), anemia (iron), goiter (iodine), night blindness (vitamin A), and rickets (vitamin D). Coincident to these scientific advances, geopolitical events – the Great Depression, World War II – greatly magnified attention on food shortages and nutrient inadequacy. Indeed, the first Recommended Dietary Allowances originated in 1941 by order of President Franklin Roosevelt, when he convened the National Nutrition Conference on Defense to ensure a population fit for war by minimizing nutrient deficiency diseases.13,14 That same year, the American Medical Association declared that, “research in nutrition be encouraged” with primary aims of “estimating the amounts of essential nutrients in foods,” “detection of nutritional deficiency states,” and more precise determination of “optimum and minimum requirements” for each nutrient.15 Consequently, all of the first Recommended Dietary Allowances focused on nutrient deficiency, including for calories, protein, iron, calcium, thiamin, riboflavin, niacin, and vitamins A, C, and D. Based on this chance convergence of scientific and geopolitical events, US dietary guidelines over most of the 20th century emphasized prevention of single-nutrient deficiencies.14

With the modernization of agriculture, food processing, and food formulations, nutrient deficiencies rapidly receded in the United States and other high-income nations. In their place, a growing epidemic of chronic diseases was recognized. Beginning in 1980, for the first time, US dietary guidelines began to focus on chronic disease.14 The main available evidence derived from less robust study designs: eg, crude cross-national comparisons, short-term experiments of surrogate outcomes in healthy volunteers. Furthermore, after decades of emphasis on deficiency diseases, the single-nutrient paradigm continued to dominate research approaches and interpretations. Together, these factors caused oversimplified inferences on how diet influences cardiovascular disease (CVD), diabetes mellitus, and obesity. Scientists and policy makers intuitively followed earlier methods that had been so successful in reducing deficiencies: identify the relevant nutrient, establish its target intake, and translate this to recommendations. To many, saturated fat and cholesterol became the causes of CHD, and total fat became the cause of obesity. Thus, the 1980 Dietary Guidelines remained heavily nutrient-focused: “avoid too much fat, saturated fat, and cholesterol; eat foods with adequate starch and fiber; avoid too much sugar; avoid too much sodium.”

Modern evidence now demonstrates the limitations of this single-nutrient component focus. The framework of Recommended Dietary Allowances was quickly recognized as methodologically and conceptually inappropriate for chronic diseases, leading to the creation of new nutrient-based metrics (eg, Adequate Intakes; Acceptable Macronutrient Distribution Ranges) which were themselves limited by imprecise definitions and inconsistent usage.16 Furthermore, although scientific investigation of macro- and micronutrients remains essential to elucidate biological mechanisms, the complex matrix of foods, food processing, and food preparation strongly modifies the final health effects.8,9,17,18 Translation of nutrient-based targets to the public also proved difficult: few people understand or can accurately estimate without guidance their daily consumption of nutrients such as calories, fats, cholesterol, fiber, salt, or single vitamins. Most importantly, methodologic advances in nutrition science now demonstrate that nutrient-focused metrics are inadequate to explain most effects of diet on chronic diseases. Rather, cardiometabolic diseases are largely influenced not by single nutrients, but by specific foods and overall diet patterns.19–21

These historical events elucidate the current state of nutrition. Modern dietary science is surprisingly young – only 83 years have elapsed since the first vitamin was isolated – and much of its existence was focused on single-nutrient diseases. The major impact of diet on chronic diseases was not widely appreciated until even more recently, 35 to 40 years ago. And, not until the last 15 to 20 years has the scientific methodology become sufficiently advanced to provide strong, consistent inference on diet, chronic diseases, and relevant metabolic pathways. Thus, the present period is one of exciting, rapid transition away from single-nutrient theories and simple surrogate outcomes and toward foods, dietary patterns, and evaluation of clinical end points. This transition forms the basis for our modern understanding of diet and cardiometabolic health.

Dietary Patterns

Dietary patterns represent the overall combination of foods habitually consumed, which together produce synergistic health effects. Evidence-informed beneficial diet patterns share several key characteristics (Table 2).19,21–23 These include more minimally processed foods such as fruits, nuts/seeds, vegetables (excluding russet or white potatoes), legumes, whole grains, seafood, yogurt, and vegetable oils; and fewer red meats, processed (sodium-preserved) meats, and foods rich in refined grains, starches, and added sugars. Such diets are higher in fiber, vitamins, antioxidants, minerals, phenolics, and unsaturated fats, and lower in glycemic index, glycemic load, salt, and trans fat.

Table 2. Dietary Priorities for Cardiometabolic Health* Goal* One Serving Equals… Examples Consume more Fruits 3 servings/d 1 medium-sized fruit; ½ cup of fresh, frozen, or unsweetened canned fruit; ½ cup of dried fruit; ½ cup of 100% juice Blueberries, strawberries, apple, orange, banana, grapes, grapefruit, avocado, mango. Whole fruits are preferable to 100% juice, which should be limited to no more than 1 serving/d. Nuts, seeds 4 servings/wk 1 ounce Almonds, walnuts, peanuts, hazelnuts, cashews, pecans, Brazil nuts, sunflower seeds, sesame seeds. Vegetables, including legumes (excluding russet or white potatoes) 3 servings/d 1 cup of raw leafy vegetables; ½ cup of cut-up raw vegetables, cooked vegetables, or 100% vegetable juice Spinach, kale, and other green leafy plants; broccoli, carrots, onions, peppers; peas, beans, lentils. Minimize starchy vegetables, especially russet or white potatoes. Whole grains† 3 servings/d, in place of refined grains 1 slice of whole-grain bread; 1 cup of high-fiber, whole-grain cereal; ½ cup of cooked whole-grain rice, pasta, or cereal Oats, bulgur, whole-wheat couscous, barley, whole-grain breads and cereals, brown rice. Fish, shellfish ≥2 servings/wk 3.5 ounces (100 g) The best choices are oily fish such as salmon, tuna, mackerel, trout, herring, and sardines. Dairy products, especially yogurt and cheese ‡ 2–3 servings/d 1 cup of milk or yogurt; 1 ounce of cheese Whole-fat or low-fat yogurt, cheese, milk. Vegetable oils 2–6 servings/d 1 teaspoon oil, 1 tablespoon vegetable spread The best evidence supports phenolic- and unsaturated fat–rich oils such as soybean, canola, and extra virgin olive oil; also consider safflower oil, peanut oil, and soft margarine spreads made with these oils. Consume less Refined grains, starches, added sugars† No more than 1–2 servings/d 1 slice of bread, ½ cup of rice or cereal, 1 sweet or dessert White bread, white rice, most breakfast cereals, crackers, granola bars, sweets, bakery desserts, added sugars. Processed meats No more than 1 serving/wk 1.75 ounces (50 g) Preserved (sodium, nitrates) meats such as bacon, sausage, hot dogs, pepperoni, salami, low-fat deli meats (eg, chicken, turkey, ham, beef). Unprocessed red meats No more than 1–2 servings/wk 3.5 ounces (100 g) Fresh/frozen beef, pork, lamb. Industrial trans fat § Don’t eat Any food containing or made with partially hydrogenated vegetable oil Certain stick margarines, commercially prepared baked foods (cookies, pies, donuts, etc0), snack foods, deep-fried foods. Sugar-sweetened beverages Don’t drink 8 ounces of beverage; 1 small sweet, pastry, or dessert Sugar-sweetened soda, fruit drinks, sports drinks, energy drinks, iced teas. Sodium No more than 2000 mg/d n/a Sodium is commonly high in foods as a preservative or to mask unpleasant flavors when previously cooked. Common sources include bread, chicken (often injected to increase succulence), cheese, processed meats, soups, canned foods.

The scientific concordance, controversy, and related evidence for these and other key dietary targets are variable (Table 3). As described above, this reflects the youthful nature of the science of nutrition and chronic disease, together with the remarkable advances in research and knowledge over just the past 1–2 decades.

Table 3. Selected Areas of Concordance and Controversy Related to Diet and Cardiometabolic Health* Broad Concordance and Less Controversy or Uncertainty† General Concordance but Some Remaining Controversy and Uncertainty Substantial Controversy and Uncertainty Insufficient Evidence for Meaningful Conclusions Benefits of: Fruits, nonstarchy vegetables, nuts/seeds, legumes, yogurtDietary fiber, potassiumModerate alcohol useMediterranean-style or higher fat DASH-style diet patterns Seafood, whole grainsCertain vegetable oils (eg, soybean, canola, extra virgin olive)n-3 and n-6 polyunsaturated fats, plant-derived monounsaturated fatsPhenolic compounds Cheese, low-fat milkCertain vegetable oils (eg, corn, sunflower, safflower)Total or animal-derived monounsaturated fatsCoffee, tea, cocoaVitamin D, magnesium, fish oil Whole-fat milkStarchy vegetables other than potatoesCoconut oil Harms of: Partially hydrogenated vegetable oils, processed meatsHigh sodiumSugar-sweetened beverages, foods rich in refined grains, starches, added sugarsGreater than moderate alcohol use Moderate sodiumWhite/russet potatoesHigh glycemic index/load Saturated fats, dietary cholesterolUnprocessed red meats, eggsButter Whole-fat milkPalm oil Little effect of: Total fat Total carbohydrateIsolated antioxidant vitamins, calcium Poultry100% fruit juiceTotal protein, specific amino acidsNoncaloric sweeteners Concepts of local, organic, farmed/wild, grass fed, genetic modification

The most well-studied dietary patterns are traditional Mediterranean and DASH diets (see http://circ.ahajournals.org/content/123/24/2870/T3.expansion.html). In comparison with the conventional low-fat, high-carbohydrate DASH diet, a modified DASH diet higher in vegetable fats and lower in carbohydrates – ie, more similar to a Mediterranean diet – produces larger cardiometabolic benefits.24–26 Both Mediterranean and DASH diet patterns improve a range of risk factors, reduce long-term weight gain, and are consistently associated with lower risk of clinical events.19,21,27–29 Pathways of benefit appear diverse, including effects on BP, glucose-insulin homeostasis, blood lipids and lipoproteins, inflammation, endothelial function, arrhythmic risk, and possibly coagulation/thrombosis, paraoxonase 1 activity, and the gut microbiome.20,21,30 Based on sociocultural and feasibility considerations, not every population in the world can consume a traditional Mediterranean diet. Other examples of Mediterranean-style dietary patterns, with adaption to various regions of the world, have been proposed.31

Randomized clinical trials in both primary and secondary prevention populations confirm the benefits of healthful, food-based diet patterns that were identified in prospective cohort studies and short-term interventional trials: such diets significantly reduce both cardiovascular events and diabetes mellitus.32–35 In comparison, both observational cohorts and randomized trials confirm little clinical benefit of diets focused on isolated nutrient targets, such as low-fat, low-saturated fat diets, which produce no significant benefits on cardiovascular disease, diabetes mellitus, or insulin resistance.36–39 This contrast in effectiveness of healthful, food-based versus nutrient-focused dietary targets is exemplified by comparing the results of 2 of the largest, longest-duration dietary trials ever performed (Figure 2).

Figure 2. Contrasting results of randomized controlled dietary trials focusing on isolated nutrients (Top) versus food-based diet patterns (Bottom). The Women’s Health Initiative (WHI, Top) focused on nutrient targets and reducing total fat and achieved large long-term changes in these targets, yet had no significant effect on cardiovascular disease or diabetes mellitus. The Prevención con Dieta Mediterránea (PREDIMED) trial (Bottom) focused on food-based diet patterns and increasing specific healthful foods, especially nuts and extra virgin olive oil (EVOO), with smaller dietary changes than in WHI, yet demonstrating significant reduction in cardiovascular disease and diabetes mellitus. Both trials successfully altered long-term diets, although with more modest dietary changes in PREDIMED. However, only the food-based intervention resulted in clinical benefit. CHD indicates coronary heart disease; CI, confidence interval; HR, hazard ratio; MI, myocardial infarction. Adapted from Howard et al36 with permission of the publisher. Copyright © 2006, JAMA; and Estruch et al34 with permission of the publisher. Copyright © 2013, The New England Journal of Medicine. Authorization for this adaptation has been obtained both from the owner of the copyright in the original work and from the owner of copyright in the translation or adaptation.

Based on this evidence, the 2015 Dietary Guidelines Advisory Committee concluded that low-fat diets have no effect on CVD and emphasized the importance of healthful, food-based diet patterns.21 Notably, because additives such as sodium and industrial trans fats can be added to or removed from otherwise similar commercially prepared foods, a specific emphasis on their reduction is also warranted.21

Focusing on overall diet patterns, rather than individual nutrients or foods, can also facilitate individual behavioral counseling and population dietary recommendations, because such patterns permit greater flexibility and personal preferences in diet choices.21 In addition, such patterns can lead to health benefits by means of smaller changes across several dietary factors, rather than major changes in a few factors, potentially increasing effectiveness and compliance.

People who follow vegetarian diets are often health conscious and tend toward healthful food patterns. However, vegetarianism per se is neither necessary nor sufficient for a good diet: indeed, french fries and soda are vegetarian, as are other harmful factors such as refined grains, starches, added sugars, sweets, trans fats, and sodium. Thus, a vegetarian diet is not a guarantee of health, whereas a nonvegetarian diet can be rich in healthful foods. A cardioprotective diet pattern must be characterized by the healthful foods that are included, not simply specific items to be avoided (Table 2).

Other increasingly popular dietary patterns include low-carbohydrate diets (minimizing all carbohydrates) and paleo diets (attempting to conform to food types consumed over millennia during human evolution). A main benefit of both low-carbohydrate and paleo diets is reduced refined grains, starches, and added sugars, which represent the majority of total carbohydrates and ultraprocessed foods in modern diets (see Carbohydrate-Rich Foods, below). Paleo diets also emphasize fruits, nonstarchy vegetables, nuts, and fish, each of which has health benefits. However, focus on low carbohydrate could paradoxically reduce intakes of other, healthful carbohydrate-containing foods such as fruits, legumes, and minimally processed whole grains; while paleo guidelines often recommend liberal intakes of red meats, lard, and salt and the avoidance of legumes and dairy. A maximally beneficial diet pattern should concurrently emphasize reductions in refined (not all) carbohydrates, processed meats, and foods high in sodium and trans fat; moderation in unprocessed red meats, poultry, eggs, and milk; and high intakes of fruits, nuts, fish, vegetables (excluding russet/white potatoes), vegetable oils, minimally processed whole grains, legumes, and yogurt (Figure 3).

Figure 3. Evidence-based dietary priorities for cardiometabolic health. The placement of each food/factor is based on its net effects on cardiometabolic health, across all risk pathways and clinical end points, and the strength of the evidence, as well. For dietary factors not listed (eg, coffee, tea, cocoa), the current evidence remains insufficient to identify these as dietary priorities for either increased or decreased consumption (see Table 3).

Diet Quality, Energy Balance, Obesity, and Weight Gain

Just as the science of cardiovascular risk is moving away from theories based on single-nutrient components and single-surrogate outcomes toward empirical evidence on foods and dietary patterns and clinical events, the science of obesity is moving away from simplistic ideas of energy balance, will power, and calorie counting toward the elucidation of effects of foods and diet patterns on the complex physiological determinants of long-term weight regulation. Of course, total calories matter in the short term, which is why people can initially lose weight on nearly any type of diet21 – and explaining why so many fad diets initially seem to work. In the short term, the best predictor of success is mindfulness with one’s chosen diet. However, for long-term weight maintenance and for cardiometabolic health independent of adiposity, healthful food–based patterns are most relevant (Table 2).21

Because obesity is so challenging to treat after it has developed, the primary prevention of weight gain is a promising strategy for individual patients and for populations. An average American adult gains only ≈1 lb (0.45 kg) per year,28 consistent with habitual excess energy intakes as small as ≈50 kcal/d explaining the gradual weight gain seen in many people.40 This finding accentuates just how well our body’s homeostatic mechanisms actually function to maintain long-term weight stability. Yet, when sustained over many years, this minor annual weight gain drives population obesity, eg, leading to 10 lbs weight gain over 10 years, 20 lbs over 20 years, and so on.

In many countries, the current obesity epidemic is a striking change from decades of prior relative stability; in the United States, for instance, obesity began steeply rising only about 30 years ago.41 Abdominal adiposity, which produces the largest metabolic harms, has also increased to a greater extent than overall weight in many nations, especially in younger women and certain middle-income countries.42 This modern rise in overweight and obesity is also occurring in children across most nations.43 The full long-term health consequences of adiposity in these youthful generations remain to be seen, in whom rates of type 2 diabetes mellitus, nonalcoholic fatty liver disease, dyslipidemia, and hypertension exceed anything observed at these ages in previous human history.44 The escalation of adiposity at youngest ages, including those <5 years of age, is also informative for considering potential causes. At such ages, population-wide declines in willpower, ability to count calories, or physical activity are difficult to invoke, reinforcing the likely role of environmental determinants of weight dysregulation.

Elucidating the specific dietary and nondietary determinants of long-term weight homeostasis is critical to understand and reverse the environmental changes contributing to this population imbalance. Growing evidence suggests that energy imbalance is a consequence of multiple complex, upstream effects, in particular poor diet quality (Figure 4). In other words, poor diet quality is a driver of excess diet quantity. Furthermore, independently of energy balance, diet quality influences metabolic risk and propensity toward abdominal adiposity. Mechanisms appear to include calorie-independent effects of different types of foods on satiety, glucose-insulin responses,45 liver fat synthesis,46 adipocyte function,47 visceral adiposity,48 brain craving and reward,49 and even metabolic expenditure.50 The gut microbiome also appears increasingly important; eg, probiotics in yogurt appear to interact with microbiota to reduce weight gain.28,29,51–54 In addition, independent of calories and body weight, one’s dietary pattern strongly influences metabolic dysfunction including the risk of diabetes mellitus.19,21 This is analogous to the weight-independent metabolic benefits of physical activity; diet quality has similar robust metabolic benefits (or harms).

Figure 4. Diet quality, obesity, and metabolic risk – a modern paradigm. Diet quality influences risk of adiposity through multiple pathways, including altering energy intake, energy expenditure, microbiome-host interactions, body fat composition, and metabolic function.

Based on these influences, when consumed over years, certain foods may interfere with long-term weight homeostasis, others have relatively neutral effects, and others promote healthy weight regulation (Figure 5).19,21 For long-term weight gain, food rich in refined grains, starches, and sugar appear to be major culprits.28,29 Such rapidly digested, low-fiber carbohydrates drive many obesogenic pathways.45,46,48–50 Key foods in this group include potatoes, white bread, white rice, refined breakfast cereals, crackers, sweets, soda, and other ultraprocessed foods high in starches or sugars. In contrast, intakes of other foods, such as low-fat milk and whole-fat milk, appear relatively neutral, suggesting they do not perturb the normal homeostatic mechanisms for long-term weight control.29,51 For meats, cheese, and eggs, influences on long-term weight gain appear to vary depending on whether they are consumed together with refined carbohydrates (in which case more weight gain is evident) or in place of refined carbohydrates (in which less weight gain or even relative weight loss is seen).29

Figure 5. Protein-rich foods and long-term weight gain in 3 separate US prospective cohort studies, based on 16 to 24 years of follow-up. Weight changes every 4 years are shown for each 1-serving/d increase in consumption; decreased consumption would be associated with the inverse weight changes. To convert pounds to kilograms to pounds, divide by 2.2. All weight changes were adjusted for age, baseline body mass index, sleep duration, and concurrent changes in smoking status, physical activity, television watching, alcohol use, and consumption of fruits, vegetables, glycemic load, and all of the dietary factors in the figure simultaneously. NHS indicates Nurses’ Health Study; and HPFS, Health Professionals Follow-up Study. Reproduced from Smith et al29 with permission of the publisher. Copyright © 2015, The American Journal of Clinical Nutrition.

Conversely, increased fruits, nonstarchy vegetables, nuts, yogurt, fish, and whole grains each appear to protect against chronic weight gain: the more these foods are consumed, the less the average weight gain.28,29,51,55 The mechanistic pathways underlying these observed benefits are still being elucidated, but may partly reflect opposing, protective effects in comparison with those of rapidly digested, refined carbohydrates.

Based on these complexities, choosing foods based on calorie content can lead to paradoxical dietary choices, industry formulations, and policy recommendations. For example, the US National School Lunch Programs recently banned whole milk, but allows sugar-sweetened chocolate skim milk.56 This untested intervention in 31 000 000 American children is based on hypothesized effects of total calories, total fat, and saturated fat in milk,56 rather than empirical evidence on the health effects of whole versus skim milk. Longitudinal studies suggest no harms of whole-fat milk for obesity, diabetes mellitus, or cardiovascular disease in adults28,29,51,57,58; that dairy fat may have potential benefits for diabetes mellitus59–61; that people switching to low-fat dairy products compensate elsewhere in their diet by increasing consumption of carbohydrates29; and that children who habitually drink low-fat milk gain more weight, and those who drink whole-fat milk gain less weight, over time.62–66 Many other ironies result from a calorie focus: eg, recommendations to consume fat-free salad dressing, in which healthful vegetable oils have been removed and replaced with starch, sugar, and salt; to minimize nuts because of their fat content and energy density; and to consume low-fat deli meats that are loaded with sodium.

In sum, modern evidence indicates that different foods have very different obesogenic potential depending on their influence on complex, multifactorial pathways of weight regulation. To prevent long-term weight gain, calories and portion sizes from certain types of foods should be minimized; from others, not emphasized; and from others, actually increased. Other conventional metrics – eg, total fat, energy density, even added sugar– may not reliably identify how specific foods influence weight gain.28,29,51 Consistent with this modern science, the 2015 Dietary Guidelines Advisory Committee Report emphasizes food-based, healthful diet patterns as a primary recommendation to address obesity.21

Several other lifestyle factors appear to interact with diet to influence adiposity. These include TV watching, sleep duration, circadian alignment, and possibly maternal-fetal (eg, placental) influences.28,41,67–70 For example, lower sleep duration and altered circadian rhythms are linked to greater weight gain and obesity, alter hunger and food preferences, and may influence leptin, ghrelin, insulin, and gut-peptide concentrations.28,67 Greater hours spent TV watching also independently increase obesity and weight gain28,68; 2 randomized trials in children suggest this is primarily mediated by changes in diet (rather than changes in, physical activity) owing to increased eating in front of the TV and altered food choices attributable to viewed marketing.71,72 Increasing physical activity, of course, has complementary benefits on weight maintenance and metabolic health. Other societal and environmental influences likely have additional effects, including education, income, race/ethnicity, social norms and networks, industry marketing, and local food availability.10,11,73

In sum, these complex and often insidious influences make unintended weight gain very easy. Conversely, based on these effects, modest behavioral and environmental improvements can attenuate or reverse chronic energy gaps, weight gain, and adiposity. Based on current available evidence, key diet-related priorities to reduce adiposity are reduction in refined grains, starches, sugars, and meats; limiting industry marketing especially from TV; increasing intakes of fruits, vegetables, nuts, yogurt, fish, vegetable oils, and whole grains; sleeping at least 7 to 8 hours nightly; and further elucidating maternal-fetal, microbiome, and sleep/circadian influences.

Individual Susceptibility – Genetics and Personalized Nutrition

Interest is growing in quantifying and understanding the determinants of interindividual variation in responses to diet. One aim is personalized nutrition – the ability to provide customized dietary advice specialized to each person’s unique profile of genes and other underlying characteristics.

Although candidate gene approaches have identified several potential gene-diet interactions for traits including blood cholesterol levels, a major challenge has been lack of replication.74–77 Even for better documented gene-diet interactions – eg, for the APOE locus, dietary saturated fat, and LDL-cholesterol; or for the CETP locus, alcohol, and high-density lipoprotein (HDL) cholesterol – evidence for clinical relevance of these differences remains weak.74 Large investigations pooling multiple cohorts have observed main (population) effects of either dietary influences or genes on major cardiometabolic risk factors, but evidence for interactions between diet and these genes is uncommon and, more relevantly, magnitudes of such potential interactions are often small.78–83 One of the more promising gene-diet interactions, notable in Hispanic populations, involves PNPLA3 and sugar consumption in relation to obesity and liver fat accumulation84–86; additional interaction with dietary polyunsaturated fats could also be present.87 Potential influences of diet on epigenetic changes (eg, DNA methylation) and subsequent cardiometabolic risk pathways are also of considerable interest,88 but relevant between-individual variation in these diet-epigenetic responses has yet to be identified. At present, compelling evidence is lacking to design personalized nutritional recommendations for cardiometabolic health based on genetic variation.

Other underlying individual characteristics may be better determinants of personalized guidance. For instance, carbohydrate-induced glycemic responses appear especially detrimental in women,89 suggesting the particular need for women to avoid rapidly digested carbohydrates. Other studies suggest that people with greater insulin resistance experience greater short-term weight loss with low-carbohydrate than with low-fat diets.90 Similarly, patients with diabetes mellitus, impaired glucose tolerance, or atherogenic dyslipidemia may also benefit most from reducing refined carbohydrates and increasing proteins and vegetable fats.91–93 In addition, personalized cognitive-behavioral and culturally and socioeconomically sensitive strategies increase effectiveness of clinical approaches to behavior change.94,95

Overall, although a promise of precision medicine has been promoted,96 the massive, rapid shifts in cardiometabolic disease occurring across nations and within populations over time97 demonstrate the dominant influence of environmental risk factors–and therefore the crucial importance of population approaches to address these environmental risks, including improved nutrition. In addition, population strategies to address diet, such as economic incentives, can reduce socioeconomic-related disparities in health, whereas individual-based approaches may exacerbate inequities.98,99 Evidence-based personalized approaches, especially related to underlying nongenetic characteristics, should be considered a complement to such population efforts.

Food Processing

Potential health effects of food processing are receiving increasing attention.100–102 Nearly all foods must undergo some processing to be consumed – eg, cooking, smoking, drying, salting, fermenting, preserving, heating, milling, refining. Benefits of processing include improved palatability, variety, nutrient bioavailability, shelf life, and convenience, and reduced risk of food-borne pathogens. Potential harms include loss of nutrients such as fiber, phenolics, minerals, fatty acids, vitamins, and other bioactives; increased doses and rapidity of digestion of starch and sugar; and introduction of harmful factors such as sodium, other preservatives, trans fats, heterocyclic amines, advanced glycation end products, and other compounds.

Many healthful foods are minimally processed (eg, fruits, nuts, seafood), whereas several classes of processed foods are harmful (eg, refined grains and cereals, preserved meats and other high-sodium foods, food made with partially hydrogenated oils). This can lead to an impression to always select “natural” and always avoid processed or ultraprocessed foods. Because many minimally processed foods are healthful, and many more highly processed foods are not, this can serve as a useful general rule. However, it is not absolute. For example, some more natural foods such as eggs, butter, and unprocessed red meats are not linked to improved cardiometabolic outcomes (see Foods, below), whereas other packaged or processed foods (eg, nut- and fruit-rich snacks, phenolic- and polyunsaturated-rich vegetable oils and margarines) improve cardiometabolic health.

Consequently, both the type of food and its processing are relevant. Rather than focusing only on natural versus processed, the clinician, consumer, policy maker, and food producer should emphasize foods that are both innately healthful and less processed; and reject foods rich in refined grains, starch, and added sugars and harmful additives such as sodium and trans fat (Table 2). In addition, as the global food system moves toward more processed foods,103 further rigorous investigation is needed to define and disseminate methods for optimal processing, rather than an impractical focus on complete absence of processing.

Dietary Supplements, Functional Foods

Use of dietary supplements, often at high or pharmacological doses, is commonplace, despite the absence of convincing evidence for health benefits. Many supplements have been evaluated in observational studies and controlled trials as potential therapies to prevent CVD or other conditions (Table 4).104–110 Evaluated doses in such trials have often exceeded usual or even recommended dietary intakes, often under the assumptions that higher levels would produce greater benefits, and that there was little risk of harm. Evidence has accrued that most of these supplements have little CVD benefit, and that certain supplements including β-carotene, calcium, and vitamin E may even be harmful.105–108,111–113 Presently, fish oil may be considered as a supplement for CVD prevention, especially among patients with prevalent CHD, based on reduction of cardiac death109 (see Fish, above). Overall, the current evidence does not support use of other dietary supplements to duplicate or complement the cardioprotective benefits of consumption of healthful foods.

Table 4. Selected Dietary Supplements and Cardiovascular Health – Summary of the Evidence β-Carotene Some cohort studies have linked low serum levels or low dietary intake of β-carotene with higher CVD risk. Trials of β-carotene supplements document no benefit in the general population and increased risk of lung cancer in patients who were at high risk of lung cancer. Calcium Meta-analysis of trials suggests that calcium supplementation could increase the risk of myocardial infarction. No evidence for cardiometabolic benefits. Vitamin D Evidence from observational studies indicates that low serum vitamin D levels, which are largely determined by sun exposure, are associated with higher risk of CVD. Trials of vitamin D supplementation have not shown reductions in risk of CVD. Additional trials using higher doses of vitamin D supplementation are ongoing. Vitamin E Several prospective cohort studies have linked vitamin E consumption or supplementation with lower risk of CHD. Trials have failed to show reductions in CVD events with supplemental vitamin E, and 2 meta-analyses suggest that high-dose vitamin E supplements may increase total mortality. Folic acid, Vitamins B 6 , B 12 Observational studies have associated low folate intake, low serum folate levels, and high homocysteine levels with higher risk of CVD outcomes. Trials have confirmed that folic acid supplementation lowers blood homocysteine levels. Long-term trials have not documented benefits of folic acid with or without vitamin B 6 and vitamin B 12 on CVD outcomes. In some trials, supplemental folic acid was associated with increased risk of CVD. Fish oil Multiple cohort studies have documented an inverse relationship between fish intake and subsequent CHD, in particular, CHD death. A meta-analysis of trials, largely in higher-risk populations, demonstrated a reduction in cardiac death with fish oil supplementation, largely because of the benefits in patients with prevalent CHD. Multivitamins Although some cohort studies have seen lower CVD risk with multivitamin supplements, several trials, rated to be of fair to poor quality, have not documented any clear CVD benefit of multivitamin use in mixed populations.

Similar to dietary supplements, functional foods attempt to improve health by incorporating bioactive compounds that may alter lipid, vascular, and other metabolic pathways, microbiome composition and function, and digestive and inflammatory systems.114–121 Such putative compounds include specific peptides, fatty acids, phenolics, vitamins, dietary fibers, prebiotics/probiotics, and plant sterols/stanols. Many of these bioactive compounds have demonstrated effects on cardiovascular risk pathways in animal and human studies; effects on blood lipids have been most often studied. To date, the potential impact of these and other promising functional foods on clinical end points is generally not established and requires investigation.

Based on cholesterol-lowering effects, some organizations suggest that functional foods with plant sterols/stanols can be considered for people with higher cholesterol levels who do not qualify for or have insufficient response to pharmacotherapy116; although others have concluded that plant sterols/stanols could have unacceptable toxicities.122,123 In the Prevención con Dieta Mediterránea (PREDIMED) trial, supplementation with extra virgin olive oil or mixed nuts, combined with advice to consume a Mediterranean-type diet, led to significant reductions in cardiovascular events,34 suggesting that these more natural foods could be considered as evidence-informed functional foods to reduce CVD events.

Emerging Issues: Organic, Genetic Modification

Public and media attention have increasingly considered whether foods are organic (ie, produced without artificial chemicals or pesticides) or genetically modified. Compared with conventionally grown foods, organically grown foods can contain higher concentrations of phenolic compounds and fewer pesticide residues; yet, they also have similar nutrient profiles in many other respects.124–126 Evidence for the health relevance of the observed differences in certain trace compounds has generally not been identified and remains controversial.127–129

Genetic modification uses biotechnology to alter crop or livestock genes to improve insect or virus resistance, herbicide tolerance, nutritional qualities, or resistance to environmental stressors. In light of challenges in population growth, global climate, soil and water availability, and changing pathogens, genetic modification holds promise to improve production, healthfulness, and sustainability. Several groups reviewing the evidence for the health hazards of genetic modification have found no evidence for harms130–134; however, methods for such evaluation remain heterogeneous.135–139 Based on first principles, genetic modification should be considered a tool, not an end point: its potential effects on human health (positive, neutral, negative) will relate to the specific compositional changes in the food, not to the method itself.140

Based on current evidence, whether a food is organic or genetically modified appears to be of relatively small health relevance in comparison with the overall types of foods and diet patterns actually consumed (Table 2). Health and environmental effects of both organic and genetically modified foods require continued evaluation as these technologies progress.

Foods and Cardiometabolic Health

Individual foods represent a complex matrix of fatty acids, proteins, carbohydrate quality, micronutrients, phytochemicals, and preparation and processing methods that together modify cardiometabolic risk.9,141 Inference on the health effects of different foods is optimally derived from well-designed prospective observational and interventional studies of clinical end points, together with supportive evidence from interventional studies of surrogate risk markers. Relevant mechanisms and pathways are further informed and elucidated by animal and experimental models. Cardiometabolic effects of different foods can be envisioned along a spectrum of benefit versus harm (Figure 3): when considering the health effects of any food, it is important to consider: compared with what?

Fruits, Nonstarchy Vegetables, Legumes, Nuts/Seeds

Minimally processed, plant-derived foods such as fruits, nonstarchy vegetables, beans/legumes, and nuts/seeds are consistently linked to better cardiometabolic outcomes (Figure 6).142–145 These observed long-term benefits are supported by controlled trials of surrogate outcomes and clinical end points using dietary patterns rich in these foods.19–21 The effects of specific subtypes of these foods are less well established. The foods richest in phytochemicals (eg, berries, nuts) appear to be particularly potent.

Figure 6. Meta-analyses of foods and coronary heart disease, stroke, and diabetes mellitus. BMI indicates body mass index; CHD, coronary heart disease; CI, confidence interval; CVD, cardiovascular disease; PC, prospective cohort; RCT, randomized clinical trial; and RR, relative risk.

Starchy Vegetables

Potatoes are a widely consumed starchy vegetable. Although potatoes contain fiber, potassium, vitamins C and B6, and other trace minerals, they predominantly contain starch (long chains of glucose) that is rapidly digested in the mouth and stomach. This high-glucose load and rapid digestion would predict cardiometabolic harms, similar to white rice and white bread (see Carbohydrate-Rich Foods, below). Relatively few long-term studies have assessed potatoes and cardiometabolic outcomes. Among those that have, higher intake of potatoes, including boiled and baked potatoes, is prospectively linked to higher incidence of diabetes mellitus, whereas potatoes, corn, and peas are linked to greater long-term weight gain, in contrast to nonstarchy vegetables that are associated with protection against weight gain and diabetes mellitus.28,55,146,147 Potatoes have also been cross-sectionally linked to greater diabetes mellitus, higher blood glucose, and lower HDL-cholesterol,148 and, in retrospective studies, higher risk of stroke.149 Based on these concerns, russet/white potatoes are generally excluded from recommendations to increase vegetable consumption.

The long-term effects of other specific varieties of potatoes or other starchy vegetables are less established. Cassava is starch-rich, similar to peeled potatoes, but the long-term cardiometabolic effects remain uncertain150,151; glycemic responses may be ameliorated by its consumption in mixed meals. Similarly, the long-term health effects of yams, sweet potatoes, and parsnips (which each tend to contain relatively less starch relative to fiber compared with russet or white potatoes), corn (which can be considered either a grain or vegetable), and peas (which is a legume) are not well established. In recent work, among major vegetables consumed in the United States, potatoes, corn, and peas were each associated with long-term weight gain, whereas other vegetable subtypes were each associated with weight loss.55

Based on high-starch content, greater glycemic responses, and some adverse long-term associations with clinical endpoints, high intakes of potatoes are not advisable. If consumed, small portion sizes, including the (nutrient-rich) skin, and mixed meals (eg, mixed with healthful foods such as vegetable oils, fish, nonstarchy vegetables) would be prudent.

Carbohydrate-Rich Foods

Carbohydrate-rich foods comprise about half or more of all calories in most diets globally. Although total carbohydrate consumption has little relation to cardiometabolic health, the quality of carbohydrate-rich foods is linked to risk (Figures 6 and 7).152–160 Notably, the conventional chemistry-based classification of simple (sugar) versus complex (starch) carbohydrates has little physiological relevance, because saccharide chain length has little influence on digestion rate or metabolic effects of different carbohydrates. More meaningful characteristics include dietary fiber content, glycemic responses to digestion, processing (intact, partially milled, fully milled, liquid), and whole-grain content.19

Figure 7. Meta-analyses of nutrients and coronary heart disease, stroke, and diabetes mellitus. CHD indicates coronary heart disease; CI, confidence interval; LA, linoleic acid; PC, prospective cohort; RCT, randomized clinical trial; RR, relative risk; and SFA, saturated fatty acid.

Each of these metrics can be altered relatively independently (Figure 8). Whole grains include endosperm (starch), bran (fiber, protein, B vitamins, minerals, flavonoids, tocopherols), and germ (protein, fatty acids, antioxidants, phytochemicals). When whole grains are intact (eg, quinoa) or partially intact (eg, steel-cut oats, stone-ground bread), the bran protects the starchy endosperm from oral, gastric, and intestinal digestion, thereby reducing glycemic responses. In finely milled whole-grain products (eg, most whole-grain breads, breakfast cereals), the bran (fiber) and germ content remain similar, but the exposed endosperm can be rapidly digested, resulting in higher glycemic responses. When the bran and germ are removed entirely (eg, refined grains: white bread, white rice, most cereals and crackers), only starchy endosperm remains, with high glycemic response and containing little fiber, minerals, or other nutrients. Some high-starch vegetables (eg, russet or white potatoes) have similar metabolic characteristics as refined grains (see Starchy Vegetables, below). Refined grains and high-starch vegetables are digested rapidly, with blood glucose and insulin responses that can be similar to simple sugars. Finally, sugars in liquid form (eg, soda, sports drinks, sweetened ice teas) appear even less satiating and more obesogenic than equivalent sugar in solid form (see Sugar-Sweetened Beverages, Noncaloric Sweeteners; and Carbohydrates, Added Sugars, Fructose; below).

Figure 8. For defining carbohydrate quality, several characteristics appear to independently alter the cardiometabolic health effects of carbohydrate-rich foods. These include whole-grain content (top left panel), ie, based on the content of milled, semiprocessed, or intact whole grain including the bran and germ; fiber content (top right panel), influenced largely by the content of bran; food structure (bottom left panel), in particular, whether the food is solid or liquid (such as sugar-sweetened beverages); and glycemic response (bottom right panel), determined by the amount and accessibility of starch and sugar. GI indicates glycemic index.

Based on these effects, refined grains (starchy endosperm without the bran or germ), other starch-rich foods (eg, white potatoes), and added sugars appear to induce relatively similar cardiometabolic harms. When starch enters the mouth without the natural shelter of a whole-grain or fiber-rich food structure, oral amylase promptly initiates its breakdown into free glucose, a process rapidly completed in the upper small intestine. Consequently, refined grains such as white bread, corn flakes, and rice; starchy foods such as russet or white potatoes; and pure table sugar all produce brisk rises in blood glucose and insulin (known as their glycemic index; or, when multiplied by portion size, as their glycemic load).161 This rapid digestion may induce multiple adverse effects, potentially stimulating reward/craving areas in the brain, activating hepatic de novo lipogenesis, increasing uric acid production, and promoting visceral adiposity.49,162–166 In addition, high glycemic load diets may even reduce total energy expenditure.50

In addition to direct harms, low-quality carbohydrates such as refined grains, certain potatoes, sugar-sweetened beverages (SSBs), and sweets may increase cardiometabolic risk by displacing other, healthier foods in the diet, eg, fruits, vegetables, nuts, legumes, and minimally processed whole grains. Consistent with this constellation of adverse effects, poor-quality carbohydrates are associated with long-term weight gain, diabetes mellitus, and CVD.29,89,158,167 Harms appear to be larger in women89,167 and others predisposed to insulin resistance and atherogenic dyslipidemia, and smaller in men and in younger, lean individuals with high physical activity.

Based on their adverse effects and pervasiveness in modern diets, reducing refined grains, starches, and added sugars is a major dietary priority for cardiometabolic health.21 Although SSB intake is declining in the United States, intakes of added sugars in other foods and, even more so, of refined grains continue to represent a major part of the diet. Currently, nearly 3 in 4 Americans consume too many refined grain products.21 Indeed, many people seek out these products, erroneously believing they are beneficial based on their promotion as low-fat or fat-free foods. Recognizing this pervasive confusion, the 2015 Dietary Guidelines Advisory Committee specified that, “consumption of ‘low-fat’ or ‘nonfat’ products with high amounts of refined grains and added sugars should be discouraged.”21 Because of the multiple independent characteristics that influence carbohydrate quality (eg, fiber, glycemic response, processing, whole-grain content), no single criterion appears perfect for distinguishing carbohydrate-rich foods. Among several recommended metrics, a ratio of total carbohydrate to dietary fiber (g/serving) of <10:1 is a helpful practical guide to identify more healthful grain choices.168,169

Meats

Similar to many other foods, guidelines on meat consumption in cardiometabolic health were historically based on minimally adjusted ecological comparisons and theorized effects of isolated nutrient content (eg, saturated fat, dietary cholesterol). However, modern evidence supports relatively neutral cardiovascular effects of saturated fat and dietary cholesterol and more relevant effects of other compounds in meats, such as heme iron, sodium, and other preservatives (see Nutrients and Cardiometabolic Health, below).

Consistent with these findings, although a minority of individual studies suggest similar cardiovascular risk for unprocessed red meat versus processed meats,170,171 many other individual studies and meta-analyses support a much stronger effect of processed meats, including low-fat deli meats, on CVD (Figure 6).172–174 Based on the observed effect sizes and relationships seen with other, noncardiovascular outcomes, residual confounding could explain some or all of the observed modest associations of unprocessed red meat with CVD.175 In contrast, the observed association of processed meats with CVD is quite plausible: much of it can be explained merely by the predicted effects of the high levels of sodium (~400% higher in processed meats) on BP levels and the subsequent effects of this elevated BP on clinical endpoints.176 Diet-microbiome interactions may also play a role,177 although such interactions would predict similar or stronger risk for unprocessed red meats than processed meats, when in fact the reverse is seen in many populations.

Interestingly, both red and processed meats, regardless of fat content, are linked to a higher incidence of diabetes mellitus, although with approximately double the risk, gram-for-gram, for processed meats than for unprocessed red meats.172,178 Mechanisms require further study, but this observed risk for diabetes mellitus may be linked to iron content179,180 and possibly lipid and amino acid metabolites, advanced glycation end products, trimethylamine N-oxide, and nitrates/nitrites.181,182

In sum, these findings provide little support for conventional guidelines to choose meats based on fat content, ie to focus on selecting lower-fat or lean meats. Rather, it would be prudent to consume small amounts of unprocessed red meats (eg, 1–2 servings/wk) to obtain readily bioavailable iron and zinc, while minimizing or entirely avoiding processed meats such as bacon, sausage, salami, and low-fat processed deli meats (chicken, turkey, pork, roast beef).183

Differences in bovine feeding systems can influence nutrient contents of meats. For example, in comparison with grain, grass feeding results in less intramuscular fat and therefore, when visible (extramuscular) fat is trimmed away, higher contents of omega-3 polyunsaturated fats, conjugated linoleic acid, and vitamins A and E, and lower contents of saturated, monounsaturated, and trans-18:1 fats.184,185 However, although grass feeding consistently increases the relative proportions (as a percent age of total fatty acids) of omega-3 fats, the absolute content (g per 100 g beef) can be the same, higher, or even lower because of decreased total fat content of the meat.184,185 Thus, the health implications of grass feeding and these modest nutrient differences require further study.

Poultry, Eggs

Relatively few studies have focused on poultry as a risk factor for CVD or diabetes mellitus, with few systematic reviews or meta-analyses (Figure 6).174 In several large studies, poultry is not significantly associated with CVD events;174,186–189 and in other cohorts, with modestly lower risk of CVD, with smaller observed benefits than seen for fish, nuts, or legumes.52,53 Large studies evaluating poultry and incident diabetes mellitus have shown mixed results including higher risk, no risk, and lower risk.178,190–195 These conflicting findings do not permit a strong inference on the cardiometabolic effects of poultry.

Egg consumption has no significant association with incident CVD in general populations (Figure 6).196,197 Conversely, eggs may influence and interact with diabetes mellitus.197 Frequent consumers (7+ eggs/wk) have higher new-onset diabetes mellitus; and among patients with prevalent diabetes mellitus, frequent consumers experience more clinical CVD events. On the other hand, higher egg consumption is associated with lower risk of hemorrhagic stroke,196 potentially related to the protective effects of dietary cholesterol on vascular fragility.198,199 As with poultry, the relevance of these conflicting findings remains uncertain. Overall evidence suggests small cardiometabolic effects of occasional consumption (eg, up to 2–3 eggs/wk); and possible harm with frequent consumption, especially among diabetics patients. Of note, the 2015 Dietary Guidelines Advisory Committee concluded that dietary cholesterol is not a “nutrient of concern for overconsumption,”21 based on low mean population cholesterol intake and no appreciable relationships between dietary cholesterol and serum cholesterol or clinical cardiovascular events in general populations.21a

In sum, occasional consumption of poultry and eggs appears relatively neutral for cardiometabolic health, without strong evidence for either risks or benefits. Until more evidence is generated, it may be prudent to consider these foods as healthful alternatives to harmful foods (eg, processed meats, refined grains, sugars) and yet as relatively unhealthy alternatives in comparison with beneficial foods (eg, fish, nuts, legumes, fruits).

Fish

The cardiovascular effects of fish and omega-3 consumption have been studied for decades. In comparison with little or no consumption, moderate consumption of fish (≈2+ servings/wk) and long-chain omega-3 (≈250 mg/d) associates with lower risk of fatal CHD (Figures 6 and 7).200–202 In contrast, higher intakes do not appear to appreciably reduce risk further. In comparison with fatal cardiac events, fish consumption has weaker associations with nonfatal cardiac events and with stroke.201,203,204 The specificity for fatal CHD, rather than all CVD events, suggests that this association may not be fully explained by residual confounding. This finding is also consistent with meta-analyses of randomized fish oil trials that demonstrate risk reductions for cardiac death, but not total CVD, CHD, or stroke.109 However, these latter pooled results obscure the differences in results of individual randomized trials over time: 4 of 5 earlier trials, yet none of several newer trials, demonstrate benefits.205 These discrepant results could be attributable to more aggressive lipid- and BP-lowering drug treatment in recent trials. Alternatively, because the dose-response effect of omega-3’s for fatal CHD appears nonlinear,200,201 higher background intakes of fish among subjects enrolled in more recent trials may have diminished the ability to detect any benefits of adding fish oil.205 Additional clinical trials of fish oil supplements are ongoing,206 but may not be adequately powered to evaluate fatal (rather than total) CHD or subgroups with low fish intake, for whom the benefits appear most plausible.

Notably, in meta-analyses of multiple controlled interventions, fish and omega-3 consumption improve major physiological risk factors for CVD including BP, heart rate, endothelial function, triglycerides, and adiponectin.201,205 Omega-3s also reduce inflammatory biomarkers, reduce myocardial oxygen use, and enhance cardiac function.201,205 Overall, although the null results of recent fish oil trials are concerning, the cumulative evidence from observational studies, clinical trials, and controlled interventional studies continues to favor plausible cardiovascular benefits of modest dietary fish consumption, in particular for the endpoint of CHD death. Based on conflicting findings from recent trials, fish oil supplementation has uncertain benefits but an excellent safety profile and may be considered as an adjunct to fish intake or for high-risk patients who do not eat fish.

The effects of fish consumption on other vascular conditions including stroke, heart failure, atrial fibrillation, and cognitive decline remain unclear, with conflicting findings.201,203,207,208 Fish and omega-3 intake also have little association with the risk for diabetes mellitus, although protective associations are seen in Asian populations209–211 and fish oil supplementation modestly raises adiponectin.212 Types of fish consumed and preparation methods may influence cardiometabolic effects, with greatest benefits perhaps obtained from nonfried, dark-meat (oily) fish that contain up to 10-fold higher omega-3 fatty acids than white-meat fish.201

Growing evidence suggests that the presence of persistent organic pollutants (eg, dioxins, polychlorinated biphenyls) may partly reduce cardiometabolic benefits of fish consumption213–215; less evidence suggests a potential for net harm, due to the countervailing benefits of omega-3s. Methylmercury consumed from fish has no detectable influence on incident cardiovascular events, hypertension, or diabetes mellitus.216–218 To optimize neurodevelopment in their children attributable to the benefits of fish consumption, women who are or may become pregnant or nursing should follow US Food and Drug Administration guidance to eat 2 to 3 servings/wk of a variety of fish lower in mercury, while avoiding only selected specific species (Gulf of Mexico tilefish, shark, swordfish, king mackerel; albacore tuna up to 6 oz/wk).219

While patients often ask about health effects of farmed (aquaculture) versus wild-caught species, few species are commonly available as both: most are either predominantly farmed (eg, tilapia, catfish, carp, shrimp, oysters) or wild-caught (eg, tuna, pollock, crab, cod).220 One exception is salmon, of which about one-third are wild-caught (principally from Alaska) and two-thirds are farmed (eg, from Norway, Chile). Because farmed salmon are fed, while wild salmon hunt for their food, farmed salmon have similar or higher levels of omega-3 fatty acids201 and likely similar net health benefits.200

Milk, Cheese, Yogurt

The cardiometabolic effects of different dairy foods represent a major unanswered question of modern nutrition science. Most dietary guidelines simply group different types together (eg, grouping milk, cheese, and yogurt as “dairy”), categorize these by fat content, and then recommend selection of low-fat products.21 Such recommendations largely derive from theoretical considerations about selected single nutrients (calcium, vitamin D, calories, saturated fat), rather than empirical evidence on health effects of the actual foods.

In longitudinal studies evaluating habitual intakes of dairy foods, relationships with CVD and diabetes mellitus do not consistently differ by fat content but appear more specific to food type: eg, cheese, yogurt, milk, butter (Figure 6).57,221–226 For example, the intake of yogurt, but not milk, is consistently associated with lower incidence of diabetes mellitus, whereas the intake of cheese, which has high calorie, fat, and saturated fat content, is also associated with lower diabetes risk in several although not all studies.57,179–184,224,226–228 Although total milk intake is generally unassociated with diabetes mellitus, fermented milk is linked to lower risk,57,227,229 suggesting a potential influence of fermentation, particularly in light of the separate findings for cheese. Bacterial cultures used for fermentation can synthesize vitamin K2 (menaquinones), which may improve insulin sensitivity.230,231 These findings suggest that the health effects of dairy may depend on multiple complex characteristics, eg, probiotics in yogurt, fermentation of cheese. The metabolic effects of specific dairy foods and fermented products represent promising areas for further investigation.

In short-term randomized trials, adding milk or dairy to energy-restricted diets increases lean mass and reduces body fat, whereas no significant body compositional effects are seen when adding dairy to ad libitum diets.232,233 Long-term effects may vary by the type of dairy. For instance, children who drink more low-fat milk gain more weight, whereas those who drink more whole-fat milk gain less weight, over time.62–66 In longitudinal studies among adults, neither low-fat nor whole-fat milk are appreciably related to chronic weight gain.28,29,51 This lack of difference may relate to caloric compensation: when adults consume more low-fat dairy, they compensate in the long term by increasing their consumption of carbohydrates.29

The STRIP trial randomly assigned 1062 Finnish infants to dietary intervention versus control, with follow-up for up to 20 years. For the first 3 years, the intervention focused on lowering total fat and saturated fat, while also increasing unsaturated fats from canola oil, other vegetable oils, and fish. At 3 years, no differences were seen in body weight, even among children most compliant with the low-fat diet.234 Subsequently, the intervention group received comprehensive dietary counseling, including to replace saturated fat with unsaturated fat, reduce salt intake, replace refined grains/cereals with whole grains, increase dietary fiber, increase fruits and vegetables, avoid smoking, and be physically active.235 The control group received only basic health education. Unsurprisingly, this comprehensive lifestyle advice, in comparison with no intervention, improved metabolic health.235 These results provide little inference on the specific effects of lowering saturated fat or dairy fat among children.

The impact of cheese consumption on long-term weight may vary depending on how it is consumed: more weight gain is seen when cheese is accompanied by refined carbohydrates, and less weight gain or even relative weight loss when cheese replaces refined carbohydrates.29 Yogurt appears protective against long-term weight gain,28,29,51 although when sugar-sweetened, approximately half the benefit appears lost.29 Animal-experimental studies and trials in humans suggest that probiotics and probiotic-microbiome interactions play a key role in the protective effects of yogurt, both for obesity and related conditions such as gestational diabetes.52–54,236–241

Interestingly, dairy fat itself may promote cardiometabolic health. In cohorts using objective blood biomarkers, greater dairy fat consumption is associated with a lower incidence of diabetes mellitus59–61,242,243 and CHD,39,244,245 and with mixed findings for stroke.246 It remains unclear whether such findings relate to health benefits of specific dairy fatty acids (eg, branched-chain fatty acids, medium-chain saturated fats, specific ruminant trans fats), other lipid-soluble factors in dairy fat, other factors in high-fat dairy foods (eg, production of vitamin K2 from fermentation of cheese), or unknown endogenous (nondietary) determinants of these blood biomarkers.247 Whatever the explanation, little evidence supports the opposing hypothesis, ie, the superiority of low-fat dairy products for health, including for risk of obesity.

In sum, dairy products represent a diverse class of foods, with complex effects that vary by specific product type and with emerging mechanistic pathways that appear to include influences of fermentation and probiotics. No long-term studies support harms, and emerging evidence suggests some potential benefits, of dairy fat or high-fat dairy foods such as cheese. Together these findings provide little support for the prevailing recommendations for dairy intake that are based largely on calcium and vitamin D contents, rather than complete cardiometabolic effects; that emphasize low-fat dairy based on theorized influences on obesity and CHD, rather than empirical evidence; or that consider dairy as a single category, rather than separately evaluating different dairy foods. The current science supports consuming more yogurt and possibly cheese; with the choice between low-fat versus whole-fat being personal preference, pending further investigation. This new evidence also calls for substantial further investment in research on cardiometabolic effects of dairy foods, including relevant components and molecular mechanisms.

Butter

In a large pooling project of European cohorts, individuals consuming any butter, in comparison with none, experienced a lower risk of diabetes mellitus.248 However, among butter consumers, no further dose-response was seen, suggesting potential for reverse causation (bias) among nonconsumers. In either case, these findings would suggest that butter is, at worst, neutral for diabetes mellitus. Butter consumption is also not significantly associated with incident CHD,223 stroke,222 or total mortality58 (Figure 6). Remarkably few studies have reported on these relationships, suggesting potential for publication bias. Because such bias would skew toward the reporting of large associations, the absence of significant associations in published reports makes it implausible that multiple other studies have identified but not reported harmful relationships. Increases in butter consumption are associated with modestly greater long-term weight gain.29 In sum, butter appears relatively neutral for cardiometabolic health, consistent with findings for total saturated fat (see Saturated Fat, below); and slightly adverse for long-term weight regulation.

Vegetable Oils

The cardiometabolic effects of vegetable oils have conventionally been considered in light of their fatty acid composition, ie, of monounsaturated, polyunsaturated, and saturated fats (see sections on each of these fats, below). Emerging evidence suggests that health effects may also relate to other constituents, in particular, flavonoid (phenolic) compounds (see Phenolic Compounds, below).30,249–252 For instance, extra virgin olive oil contains oleocanthal, a phenolic that binds cyclooxygenase (COX) 1 and 2 receptors (causing a characteristic burning throat sensation, similar to that induced by chewing no coated aspirin) and exhibits anti-inflammatory properties.30,251,252 In the PREDIMED randomized trial, participants receiving extra virgin olive oil and dietary advice to consume a Mediterranean diet experienced 30% lower risk of stroke, MI, or death, in comparison with control.34 In the intervention group, ≈60% of the extra virgin olive oil simply replaced regular olive oil, commonly used in Spain. These findings, together with mixed evidence for cardiovascular benefits of monounsaturated fats21 (see below), which represent most of the fats in olive oil, suggest that fatty acid profiles may not be the only relevant determinant of health effects of oils.

Little investigation has been done on the long-term health effects of tropical oils, such as palm or coconut. These oils contain saturated fat, but also other compounds, eg, medium-chain fatty acids in coconut oil that could have health benefits.253 Modern nutritional science has demonstrated the limitations of drawing conclusions about health effects of any food product based on theories about its nutrient contents.9 Thus, long-term investigations are urgently needed to make evidence-informed decisions about avoiding or increasing the use of tropical oils. Industrially interesterified oils are increasingly common, but similarly without long-term evidence on their health effects or safety.254

Based on overall evidence for cardiometabolic effects, the current evidence supports generally increased consumption of vegetable oils in place of refined grains, starches, sugars, meats, butter, and lard. Among different oils, the benefits of soybean, extra virgin olive, and canola oil may be best established. Virgin oils (eg, extra virgin olive oil, virgin soybean oil) may be preferable because of their low-temperature refining that may better preserve trace phenolic compounds; further study of how processing methods of vegetable oils influence phytochemicals and health effects is needed. In the future, certain vegetable oil blends may offer particular cardiometabolic benefits, eg, combining flax and safflower oils, or canola oil and omega-3 fatty acids.255 Sufficient evidence to support strong promotion or avoidance of tropical oils is lacking. Additional metabolic and long-term studies of different specific vegetable oils, including refined and unrefined versions, are urgently needed.

SSBs, Noncaloric Sweeteners

Both long-term prospective cohorts and clinical trials demonstrate that SSBs increase adiposity.256 Per serving, SSBs associate with greater long-term weight gain than nearly any other dietary factor.28 These effects are likely attributable to their high glycemic and insulin responses and low satiation (see Carbohydrate-Rich Foods, above). SSBs are also associated with increased incidence of diabetes mellitus and CHD (Figure 6).257,258 These effects appear partly but not entirely mediated by adiposity, consistent with independent adverse effects of SSBs on other pathways such as hepatic de novo lipogenesis, visceral fat accumulation, and uric acid production (see Carbohydrate, Added Sugars, Fructose, below). Globally, SSB consumption is highest at younger ages,259 boding poorly for long-term global health if such high intake continues as these populations age. Worldwide, 184 000 cardiometabolic deaths per year are estimated to be attributable to SSB consumption.260

With growing policy attention on sugar-sweetened beverages and added sugars, the food industry is increasingly seeking low-calorie and noncaloric alternatives.261 These include artificial sweeteners (eg, saccharin, sucralose, aspartame) and natural low-calorie (also termed high-intensity or nonnutritive) sweeteners (eg, stevia). Based on long-term observational studies and intermediate-duration (eg, 2 years) clinical trials,28,256 these appear to be better alternatives than sugar for people who consume large quantities of SSBs. However, based on animal experiments and limited human data, these artificial and nonnutritive sweeteners may not be benign, with potential for impact on cognitive processes (eg, reward, taste perception), oral-gastrointestinal taste receptors, glucose-insulin and energy homeostasis, metabolic hormones, and the gut microbiome.262–265 Cognitive effects, for example, may be especially relevant in children: if tastes become accustomed to such intense sweetness, will palates and attraction be reduced for naturally sweet, healthful foods such as apples or carrots? In sum, based on limited available evidence, artificial and nonnutritive sweeteners appear to be a useful intermediate step to reduce harms of SSBs (eg, to switch from regular to diet soda) but should subsequently also be reduced (eg, to switch from diet soda to seltzer water) to prevent potential long-term harms. Other uses of such sweeteners should not yet be considered innocuous for cardiometabolic health.

100% Fruit Juice

Although SSB and 100% fruit juice have similar sugar content, the latter is linked to relatively smaller long-term weight gain.28 Furthermore, the intake of sugar-sweetened fruit juice, but not 100% fruit juice, is associated with incident diabetes mellitus in longitudinal studies (Figure 6).257,266 These findings suggest that 100% fruit juice may have other beneficial components, eg, dietary fiber, vitamins, and phytochemicals, that at least partly offset any harms. In short-term trials, fruit juice has no appreciable effects on blood pressure, cholesterol levels, or glucose-insulin homeostasis.267,268 In sum, moderate intake of 100% juice (eg, up to one serving/d) appears reasonable, especially given the low intakes of whole fruit in most populations; higher intake of 100% juice may not be prudent because of links to long-term weight gain.

Coffee, Tea

While coffee is commonly thought of in relation to its caffeine content, it represents a liquid extract of legumes (coffee beans) that contains many active compounds. Both caffeinated and decaffeinated coffee are associated with lower onset of diabetes mellitus in a dose-dependent fashion (Figure 6).269 Coffee intake also is associated with lower risk of CHD and stroke but in a nonlinear fashion: in comparison with no intake, the lowest risk is seen at 3 to 4 cups/d, with increasing risk at higher intakes.270 Several small controlled trials have evaluated the potential effects of habitual coffee consumption on cardiometabolic risk factors, with mixed and inconsistent findings to date.271–273 A Mendelian randomization study, evaluating genetic variants linked to coffee intake, did not find associations with any cardiovascular or metabolic risk factors.274

Similar to coffee consumption, tea consumption is associated with a lower risk of diabetes mellitus and CVD, especially comparing very frequent consumption (3–4 cups/d) with none (Figure 6).275,276 Yet, controlled trials of tea have not identified robust benefits on markers of glucose-insulin homeostasis.277,278 In comparison, in meta-analyses of trials, green tea, black tea, and herbal roselle tea each modestly lower BP,279–281 whereas green and black tea, but not herbal roselle tea, also lower LDL-cholesterol.282–284

Overall, observational studies support potential cardiometabolic benefits of both coffee and tea. Plausible biological mechanisms that could explain the size of these associations have not been confirmed, with the exception perhaps for tea and cardiovascular risk. Based on current data, tea and coffee do not increase cardiometabolic risk and can be safely consumed, and green and black tea may reduce cardiovascular risk. Further research on these potential benefits is needed before actively encouraging consumption as a means to reduce risk.

Alcohol

Habitual heavy alcohol use causes up to one-third of nonischemic dilated cardiomyopathy in many nations.285 Ventricular dysfunction is often irreversible, even when alcohol use is stopped; while continued drinking is associated with high mortality. Habitual alcohol and acute binges are associated with higher risk of atrial fibrillation.286 Like other liquid calories (with the exception of milk), alcohol intake also is associated with higher long-term weight gain.287 Conversely, in comparison with nondrinkers, regular moderate alcohol consumption – up to ≈2 drinks per day for men, ≈1 to 1.5 drink per day for women – is associated with lower incidence of CHD and diabetes mellitus, although not stroke.288,289 Such observational analyses could partly overestimate benefits, because never drinkers could include those who have avoided alcohol because of unmeasured factors that relate to later poor health.290 Yet, magnitudes and consistency of observed lower risks of CHD and diabetes across diverse populations, together with favorable effects on HDL-cholesterol, insulin resistance, and fibrinogen in controlled trials,291 provide strong evidence for at least some cardiometabolic benefit of moderate alcohol use. Although a common perception is that the effects are specific to red wine, cardiometabolic benefits have also been seen for white wine, beer, and spirits.292 This could relate to the physiological effects of alcohol itself,291 or the phenolics in wine and beer, as well.292

Alcohol use exhibits a “J-shape” with all-cause mortality, with lowest risk observed between 1 drink/wk and 1 drink/d, and higher risk thereafter.289 In addition, the pattern of drinking is important: benefits are seen with moderate use across multiple days per week, not with high levels on a few days.293 Across the population, alcohol produces net harms because of the increased risk of cancers, liver disease, cardiomyopathy, accidents, violence, homicides, and suicides.1,294 Thus, alcohol intake should not be recommended as a means to reduce CVD risk. Adults who already drink alcohol should be advised to limit their use to moderate levels.

Nutrients and Cardiometabolic Health

Phenolic Compounds

Bioactive polyphenols include flavonols (eg, in onions, broccoli, tea, various fruits), flavones (in parsley, celery, chamomile tea), flavanones (in citrus fruits), flavanols (flavan-3-ols) such as catechins and procyanidins (in cocoa, apples, grapes, red wine, tea), anthocyanidins (in colored berries), and isoflavones (in soy). In laboratory studies and randomized trials, flavonoid-rich cocoa has small but measurable benefits on BP, endothelial function, insulin resistance, and blood lipids.295–297 BP-lowering occurs with as little as 6.3 g/d (30 kcal/d) of commercial dark chocolate and correlates with increased endothelial nitric oxide production.298 The latter mechanism also suggests potential cardiovascular benefits beyond lower BP per se. A few short-term trials of other dietary sources (eg, tea, red wine, grapes) or specific flavonoid extracts have not consistently improved BP, lipid levels, or endothelial function.295–297 Some observational studies evaluating total or selected dietary flavonoids observe lower risk of cardiometabolic events299,300; no long-term clinical trials have been performed. The remarkable heterogeneity of different flavonoids and their dietary sources limits inference for class effects, and clinical benefits and dose-responses are not well-established. Yet, many foods with growing evidence for cardiometabolic benefits – eg, berries,301 nuts,145 extra virgin olive oil34 – are rich in phenolics, and the documented physiological effects are promising and provide clear impetus for further study.

Sodium

In North America and Europe, most sodium (≈75%) comes from packaged foods and restaurants, and a minority from home cooking or table salt; whereas in Asian countries, most sodium comes from soy sauce and salt added during cooking or at the table.302 Nearly every country in the world exceeds the recommended mean national intake of 2000 mg/d.303

Sodium raises BP in a dose-dependent fashion, with stronger effects among older individuals, people who have hypertension, and blacks.304 In meta-analyses of longitudinal studies, high sodium intakes are associated with incident total stroke, stroke mortality, and CHD mortality (Figure 7).305–307 This is supported by the strength of BP as a surrogate outcome308 and by ecological and experimental studies of sodium and CVD.304 Indeed, the latter studies suggest that chronically high sodium induces additional, BP-independent damage to renal, myocardial, and vascular tissues.309,310

Nearly all observational studies demonstrate a positive association between very high sodium intakes (eg, 4000+ mg/d) and CVD events, in particular stroke.305–307 Some studies have also observed a potential J-shaped relationship, with increased CVD risk at modest intakes (eg, <3000 g/d).311–313 These findings have generated recent controversy about the optimal lowest levels of sodium consumption.314

The assessment of sodium in observational studies, whether by urine spot, 24-hour collection, or diet questionnaire, has unique potential biases.315 These include potential for incomplete 24-hour urine collections (leading to underestimation of sodium intake, especially in less compliant, sicker individuals); reverse causation (ie, due to at-risk subjects, such as those with higher BP or diabetes mellitus, actively lowering their sodium intake); confounding by physical activity (which increases total energy consumption, that then increases total sodium intake316); and confounding by frailty and other reasons for low total energy consumption (given the very strong correlation between sodium and total energy consumption). These limitations together could explain the J-shapes seen in certain observational studies.

In comparison, during extended surveillance in a large sodium study that excluded sick individuals at baseline and collected multiple 24-hour urine samples per subject, minimizing the potential influence of these biases, participants with lowest intakes (<2300 mg/d) experienced 32% lower CVD risk than those consuming high intakes, with evidence for linearly decreasing risk.317 In ecological studies, the lowest mean intake level associated with both lower systolic BP and a lower rise in BP with aging is 614 mg/d.318 In randomized controlled feeding trials, BP reductions have been documented down to intakes of 1500 mg/d.319 In meta-analyses of prospective observational studies, the lowest mean intakes associated with lower risk of CVD events ranged from 1787 to 2391 mg/d.305 Together, these findings support the recommended target intakes in current national and international dietary guidelines, which range from 1200 to 2400 mg/d.110,313,320–323

Although large reductions in sodium can increase renin-aldosterone and serum triglyceride levels,324 the effects of more moderate, gradual reductions on these pathways are not established. It also remains unclear whether such physiological effects could offset, let alone reverse, the BP-lowering benefits of sodium reduction in order to explain the J-shaped relations with CVD risk seen in some observational studies. Overall, although adverse effects of rapid sodium reduction cannot be excluded, and true optimal lower limits remain uncertain, the sum of evidence suggests that optimal levels of sodium intake are ≈2000 mg/d193,200–204 (or lower).304 Based on a target consumption level of 2000 mg/d, 1.65 million annual global cardiovascular deaths are estimated to be attributable to excess sodium intake.304

Potassium, Calcium, Magnesium

Vegetables, fruits, whole grains, legumes, nuts, and dairy are major sources of minerals. In randomized trials, potassium lowers BP, with stronger effects among individuals who have hypertension and when dietary sodium intake is high.325 This BP lowering has been correlated with both increased urinary potassium excretion and a lower urine sodium-to-potassium ratio. Consistent with these benefits, potassium-rich diets are associated with lower risk of CVD, especially stroke (Figure 7).326 Diets rich in potassium also attenuate, whereas diets low in potassium exacerbate, the BP-raising effects of sodium. For instance, a Mediterranean or DASH-type diet (eg, richer in fruits, vegetables, nuts) reduces, whereas a typical Western diet increases, the BP-raising effects of sodium.326,327 In sum, the evidence strongly supports the importance of potassium-rich foods for reducing BP and CVD.

In short-term trials, calcium and magnesium supplements also modestly lower BP, although with substantial heterogeneity among studies. However, calcium supplements with or without vitamin D may significantly increase risk of MI in long-term randomized trials.328,329 In observational analyses, dietary and blood magnesium levels are inversely associated with CVD, especially fatal CHD330; long-term trials have not been performed. Calcium and magnesium supplements cannot yet be recommended for general CVD prevention.

Antioxidant Vitamins

Several vitamins and nutrients are associated with lower CVD risk in observational studies, but trials of supplements, including folate, B vitamins, β-carotene, vitamin C, vitamin E, and selenium, have shown no significant effects on atherosclerosis progression or CVD events.19,331,332 Most of these trials, for reasons of power, evaluated up to a few years of treatment in patients with established CVD or at high risk. In contrast, most observational studies evaluated long-term or habitual intake among generally healthy populations. Thus, discrepancies in findings could relate in part to different time periods of biological sensitivity — eg, some vitamins and nutrients could be important only early in the disease course. Such explanations require confirmation in prospective studies and trials. Discrepancies between observational studies and supplement trials may also relate to residual bias in observational studies, eg from other lifestyle behaviors (ie, observed benefits are not attributable to diet) or from other nutritional factors in vitamin-rich foods (ie, observed benefits are caused by diet but not by the specific measured vitamins or nutrients). For example, diets higher in antioxidant vitamins tend to be rich in fruits, vegetables, nuts, and whole grains, foods that contain multiple other beneficial factors including other vitamins, minerals, phytochemicals, and fiber, and being foods that can provide benefit by replacing unhealthful foods, as well. Thus, isolating one or even several components of these foods in a supplement may not produce similar effects as would occur from consuming the whole food.8,9

Vitamin D

Observational studies demonstrate links between higher plasma vitamin D, which is largely driven by sun exposure, and CVD risk; however, large trials of vitamin D supplements have shown no benefits.104 If higher plasma vitamin D proves to lower CVD risk, brief sun exposure can efficiently provide such levels in comparison with dietary intake. Ongoing trials are now testing whether higher doses of vitamin D supplements influence CVD; for now, such supplementation is not warranted as a means to improve cardiometabolic health.

Carbohydrates, Added Sugars, Fructose

For decades, carbohydrates were considered a foundation of a healthful diet, as evidenced by the placement of grain products at the base of the 1992 Food Guide Pyramid. Since that time, it has become clear that, although total carbohydrate has little influence on cardiometabolic health, the types and quality of carbohydrate have a major impact (Figures 6 and 7; see Carbohydrate-Rich Foods, above). Certain carbohydrate-containing foods (eg, fruits, legumes, vegetables, minimally processed whole grains) are protective, whereas foods rich in refined grains (eg, white bread, white rice, crackers, cereals, bakery desserts), starches (eg, russet or white potatoes), and added sugars (eg, SSBs, candy) are harmful. Because of this diversity, the cardiometabolic effects of total carbohydrate are modified by the quality of carbohydrate. For people who consume mostly low-fiber, rapidly digested, refined grains, starches, and added sugars, a lowering of total carbohydrate will produce substantial metabolic benefits. Yet, recommending a low-carbohydrate diet per se is not ideal: the focus should be on reducing less healthful carbohydrates, not all carbohydrates.

The US Food and Drug Administration has recently proposed revising the Nutrition Facts Panel to include added sugars.333 Although added sugars are not healthful, targeting added sugars alone, rather than overall carbohydrate quality, could push consumers toward foods low in added sugars but rich in equally harmful refined complex carbohydrates (eg, many breakfast cereals, breads, crackers); and away from otherwise healthful foods containing modest amounts of added sugar (eg, nuts or minimally processed whole grain–rich cereals sweetened with honey). Appropriately, the 2015 Dietary Guidelines Advisory Committee explicitly advises restriction of both refined grains and added sugars.21

Much public attention has focused on the potential harms of high-fructose corn syrup. Because glucose, the main sugar in regular corn syrup (which is mostly starch), tastes less sweet than fructose, high-fructose corn syrup has been modified to increase the fructose-to-glucose ratio to about 1:1, ie, a similar ratio as in natural sugar (sucrose) found in cane sugar, beet sugar, or honey. Consequently, there are few expected or observed physiological or health differences between high-fructose corn syrup versus sucrose.165,166,334 In contrast, there are important metabolic differences between glucose and fructose – each equally present in both high-fructose corn syrup and natural sugar (sucrose). In particular, high doses of rapidly digested glucose induce postprandial hyperglycemia, hyperinsulinemia, and related metabolic disturbances. When glycogen stores are replete, excess glucose is further converted to fat via hepatic de novo lipogenesis. In comparison, high doses of rapidly digested fructose have little influence on blood glucose or insulin levels, but more directly stimulate hepatic de novo lipogenesis, hepatic