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Lead Article Qualified health claim for whole-grain intake and risk of type 2 diabetes: an evidence-based review by the US Food and Drug Administration Sedigheh Yamini and Paula R. Trumbo The objective of this review is to explain how the US Food and Drug Administration (FDA) used its evidence-based review system to evaluate the scientific evidence for a qualified health claim on the role of whole-grain consumption in reducing the risk of type 2 diabetes. The labeling of health claims, including qualified health claims, on conventional foods and dietary supplements requires premarket approval by the FDA. Health claims characterize the relationship between a substance (food or food component) and a disease (eg, diabetes or cardiovascular disease) or a health-related condition (eg, hypertension). This review describes the FDA’s evaluation of intervention and observational studies that characterize a relationship between whole grains and type 2 diabetes. This evidence-based review provides very limited evidence to support a health claim of a relationship between intake of whole grains and a reduced risk of type 2 diabetes. INTRODUCTION Type 2 diabetes is one of the most prevalent diseases in the United States.1 The risk of developing type 2 diabetes is associated with many factors, including obesity, race, and ethnicity.1 Increased whole-grain consumption has been reported to lower the risk of weight gain/obesity and type 2 diabetes. Conflicting results reporting a beneficial effect or no effect have been reported for a relationship between whole grains and type 2 diabetes. The majority of the studies evaluated foods that US Food and Drug Administration (FDA) does not consider to be a whole grain (eg, wheat germ, bran cereals, or pearled barley). In determining what foods should be considered whole grains, the FDA is guided by its 2006 draft guidance entitled Whole Grain Label Statements.2 In this draft guidance, the FDA describes whole grains as cereal grains that consist of the intact, ground, cracked, or flaked caryopsis and whose principal anatomical components (the starchy endosperm, germ, and bran) are present in the same relative proportions as they exist in the intact caryopsis. The draft guidance listed the following examples of cereal grains: amaranth, whole-grain barley, buckwheat, bulgur, corn (including popcorn), millet, quinoa, rice, rye, oats, sorghum, teff, triticale, wheat, brown rice, and wild rice. The addition of individual parts of a whole grain, such as bran, to a food does not make the food “whole grain,” because such ingredients do not contain the entire grain with all its components. This review explains how the agency used its evidence-based review system3 to evaluate a qualified health claim regarding whole-grain consumption and type 2 diabetes, using the FDA’s definition of whole grain. HEALTH CLAIMS The Nutrition Labeling and Education Act of 1990 authorized the FDA to allow a health claim statement on Affiliation: Sedigheh Yamini and Paula R. Trumbo are with the Office of Nutrition and Food Labeling, Center for Food Safety and Applied Nutrition, US Food and Drug Administration, College Park, Maryland, USA. Correspondence: S. Yamini, 5100 Campus Dr, HFS – 830, College Park, MD 20740, USA. Email: [email protected]. Phone: þ1-240402-1681. Key words: diabetes, health claim, type 2 diabetes, whole grains. Published by Oxford University Press on behalf of International Life Sciences Institute 2016. This work is written by US Government employees and is in the public domain in the United States. doi: 10.1093/nutrit/nuw027 Nutrition ReviewsV Vol. 74(10):601–611 R 601 the labeling of conventional foods and dietary supplements that describes a relationship between a substance (food or food component) and a disease (eg, cancer, type 2 diabetes) or a health-related condition. A healthrelated condition is a condition (eg, hypertension) that is essentially indistinguishable from a disease (eg, coronary heart disease) and/or is a surrogate marker for risk of a specific disease (eg, insulin resistance for type 2 diabetes). The labeling of conventional foods and dietary supplements with health claims requires premarket approval by the FDA. Health claims were first authorized by the US Congress using the significant scientific agreement (SSA) standard. The SSA standard is a rigorous standard that requires a high level of confidence in the validity of a substance–disease relationship.3 An SSA health claim is authorized through the rule-making process. In contrast to SSA health claims, qualified health claims are based on less scientific evidence and are accompanied by qualifying language to reflect the level of science supporting the claim. Qualified health claims were established for the labeling of dietary supplements after court decisions regarding First Amendment issues. The pivotal court ruling (Pearson v Shalala) concluded that the First Amendment protection of commercial speech does not permit the agency to reject health claims that it determines to be potentially misleading unless the agency also reasonably determines that a disclaimer would not eliminate the potential deception.4 A subsequent FDA initiative resulted in the establishment of qualified health claims for the labeling of conventional foods as well.5 Qualified health claims are issued through letters of enforcement discretion. When a letter of enforcement discretion has been issued, the FDA does not object to the use of the claim specified in the letter, provided the products that bear the claim are consistent with the stated criteria. Both SSAs and qualified health claims pertain to disease risk reduction in the general US population or a target subgroup (eg, women, children, or elderly) that does not have the disease that is the subject of the claim. EVIDENCE-BASED REVIEW OF HEALTH CLAIMS BY THE FDA A detailed and thorough premarket review of the scientific evidence is a key part of the process for evaluating either authorized (SSA) or qualified health claims. In 2009, the FDA published a guidance document on the evidence-based review system for the scientific review of health claims.3 On the basis of this guidance, the FDA reviews all scientific evidence (eg, supportive and not supportive) related to a specific health claim that the petitioner is required to provide in support of the claim. Through a literature search, the agency identifies 602 additional studies that it considers relevant to the petitioned health claim. The agency separates individual reports of human studies from other types of data and information. The FDA focuses its review on reports of interventional and observational studies in humans, because scientific conclusions about the substance–disease relationship in humans can only be drawn from such studies. In addition to individual reports of human studies, the agency also considers data from other sources, such as meta-analyses, review articles, and animal and in vitro studies. Although this type of data and information can assist the agency in understanding the scientific issues about the substance, the disease or health-related condition, or both, it cannot by itself support a health claim relationship. The FDA evaluates the individual reports of human studies to determine whether any scientific conclusions can be drawn from each study. The human studies that lack critical criteria, such as a control group or an appropriate statistical analysis, are eliminated from further review because they cannot be the basis for scientific conclusions about the health claim relationship.6,7 Moreover, it is important that the study population is relevant to the general US population or subgroup identified in the proposed claim. Therefore, each study is evaluated to determine if the study population lives in an area where malnutrition or inadequate intakes of the specific substance are common and/or where the prevalence or etiology of the disease that is the subject of the claim is different from that in the United States (eg, risk factors for gastric cancer in certain Asian countries).3 Differences in nutrition, diet, and disease risk factors between the United States and the country where a study was conducted may mean that the study results cannot be extrapolated to the US population or population subgroup.3 Health claims are statements about reducing the risk of a disease in people who do not already have the disease that is the subject of the claim. The FDA may consider evidence from studies in individuals diagnosed with the disease that is the subject of the health claim only if extrapolation of that evidence to individuals who do not have the disease is scientifically appropriate. The FDA rates the relevant human intervention and observational studies for methodological quality. This quality rating is based on several criteria related to study design (eg, use of a placebo-controlled vs a non–placebo-controlled group), data collection (eg, type of dietary assessment method), quality of the statistical analysis, type of outcome measured (eg, disease incidence vs validated surrogate endpoint), and study population characteristics other than relevance to the US population (eg, selection bias and whether important information about the study subjects, such as age or smoking status, was gathered and reported).3 Nutrition ReviewsV Vol. 74(10):601–611 R Finally, the agency rates the strength of the total body of publicly available evidence by considering the following: (1) the study type (eg, intervention, prospective cohort, case–control, cross-sectional); (2) the methodological quality rating assigned; (3) the quantity of evidence (number of the various types of studies and sample sizes); (4) whether the body of scientific evidence supports a health claim relationship for the US population or target subgroup; (5) whether study results supporting the proposed claim have been replicated; and (6) the overall consistency of the total body of evidence. On basis of the totality of the scientific evidence, the FDA then determines whether such evidence is credible to support the substance–disease relationship, and, if so, either authorizes an SSA health claim or, through a letter of enforcement discretion, issues a qualified health claim that reflects the level of scientific evidence.3 SURROGATE ENDPOINTS FOR TYPE 2 DIABETES The FDA uses surrogate endpoints that have been identified by the National Institutes of Health and the FDA’s Center for Drug Evaluation and Research as qualified biomarkers for predicting the risk of a disease. In addition to the incidence of type 2 diabetes, the FDA recognizes 3 surrogate endpoints for assessing type 2 diabetes risk for purposes of a health claim evaluation: (1) fasting blood glucose concentration; (2) oral glucose tolerance; and (3) insulin resistance. Insulin resistance is assessed by various measurements of insulin sensitivity, including the euglycemic hyperinsulinemic clamp method, the homeostasis model assessment (HOMA), and the quantitative insulin sensitivity check index (QUICK1). CONSIDERATION OF THE QUALIFIED HEALTH CLAIM BY THE FDA A petition submitted to the FDA requested a qualified health claim for the relationship between the consumption of whole grains and a reduced risk of type 2 diabetes in the general US population. The petition cited 55 publications as evidence to substantiate the risk-reduction relationship for the proposed claim, including 19 human intervention studies8–26 and 23 publications27–49 examining 24 observational studies to evaluate the relationship between whole-grain consumption and reduction of risk of type 2 diabetes. In addition to these individual studies, the petition cited several publications50–59 on the history or consumption of whole grains, the history of agriculture, or the world agriculture supply and demand; diabetes data and trends; a position statement; 2 meta-analyses27,45; Nutrition ReviewsV Vol. 74(10):601–611 R and 1 systematic review.60 The publication by de Munter et al.,27 which included a meta-analysis, also reported data from 2 observational studies: the Nurses’ Health Study I (NHS I) and the Nurses’ Health Study II (NHS II). Similarly, the publication by Sun et al.45 included individual reports of 3 observational studies – the NHS I, the NHS II, and the Health Professionals Follow-Up Study (HPFS) – as well as a meta-analysis. Therefore, the FDA considered each of these publications in both the meta-analysis category and the observational studies category. In addition to the publications cited in the petition, comments provided during the public comment period for the petition identified 21 additional human intervention studies61–82 and 17 additional observational studies83–99 that evaluated the relationship between whole-grain intake and reduction of risk of type 2 diabetes. Through a literature search, the agency identified 1 additional relevant intervention study100 that evaluated the relationship between whole-grain intake and risk of type 2 diabetes. As mentioned above, the agency must be able to review the critical elements of a study to determine whether any scientific conclusions can be drawn. Therefore, review articles, meta-analyses, and reports of studies on a different substance or a disease that was not the subject of the petition could not be used.27,45,50–60 EVALUATION OF INTERVENTION STUDIES The FDA evaluated 41 reports of intervention studies that were designed to evaluate the relationship between whole-grain intake and risk of type 2 diabetes.8–26,61–82 Some of these studies evaluated the effects of whole grains as a category of food, while others were limited to single forms of whole grains (eg, brown rice, oats). Of the 41 intervention studies reviewed, scientific conclusions could not be drawn from 35 studies. For 31 of these studies,8,10,11,14–17,19–21,23,25,62–66,68–80,82 the study duration was too short (90 minutes to 12 hours) to provide any information about the long-term effect of whole-grain consumption on reduction of risk of type 2 diabetes. Such short-term studies were designed to assess the glycemic index or glycemic load of foods. The glycemic index is a function of the food’s immediate effect on blood glucose levels rather than the long-term effect of whole-grain consumption on the body’s ability to metabolize glucose, such that lower blood glucose levels may result in increased insulin sensitivity. Therefore, the agency could not draw scientific conclusions from these studies. 603 The remaining 4 studies18,22,61,67 identified their substances as whole grains that, on the basis of the FDA definition, were not considered whole grains. For example, Juntunen et al.18 considered rye bread made with added rye bran (to increase the bread’s dietary fiber content) as whole grain. Another study22 did not specify the composition of the foods studied in a manner clear enough for the FDA to determine whether the foods were actually whole grains. Another study61 investigated the effects of the Nordic diet, which contains whole grains and other high-fiber plant foods like fruits, berries, nuts, and vegetables. One intervention study investigated legumes, seeds, and vegetables in addition to whole grains.67 Because these 4 studies may have evaluated substances other than, or in addition to, whole grains contained in the diet, no scientific conclusions could be drawn about whether, specifically, whole grains may reduce the risk of type 2 diabetes. Six intervention studies were available from which scientific conclusions could be drawn about the relationship between whole-grain intake and risk of type 2 diabetes9,12,13,24,26,100 (Table 1). Andersson et al.9 conducted a high-quality randomized crossover intervention study of 30 Swedish overweight and obese (body mass index [BMI] 28 6 2 kg/m2) men (n ¼ 8) and women (n ¼ 22). These participants did not have type 2 diabetes but were at high risk, with 1 or more of the following symptoms: elevated serum insulin, elevated fasting blood glucose, elevated triglycerides, reduced highdensity lipoprotein, or borderline hypertension. The subjects followed their habitual diets but were advised to incorporate a fixed amount (112 g/d, or about 7 servings per day) of whole-grain foods (intervention group) or refined-grain foods (control group) for a period of 6 weeks in each diet. The whole-grain products provided were defined as foods for which whole grains (including the bran, germ, and starchy endosperm), mainly in milled form, provided 50% of the dry weight of the product. Both whole grains and refined grains were provided to the subjects during the study period. Compliance with the dietary intervention was monitored by diaries, including a structured list to verify daily portions eaten, and subjects adhered to their prescribed diets. Insulin sensitivity was directly measured by the euglycemic hyperinsulinemic clamp method. The subjects did not lose weight, and their insulin sensitivity and fasting blood glucose levels were not significantly different between the whole-grain and refinedgrain groups. Brownlee et al.12 conducted a high-quality 16week parallel intervention study in 266 overweight men and women (BMI >25 kg/m2) at 2 centers in the United Kingdom. The subjects were randomly divided 604 into 3 groups: group 1 (control group) (n ¼ 100; no dietary changes); group 2 (n ¼ 85; 60 g of whole grains per day for 16 weeks); and group 3 (n ¼ 81; 60 g of whole grains per day for 8 weeks followed by 120 g of whole grains per day for 8 weeks). Whole-grain foods were provided to the subjects, who were instructed to substitute refined-grain foods with an equivalent amount of whole grains. Seven-day food frequency questionnaires were used to assess compliance, and on average the subjects adhered to their assigned diets. Fasting blood glucose and serum insulin were measured to calculate insulin resistance on the basis of the QUICK1 method. There was no significant difference in fasting blood glucose or insulin resistance between either of the intervention groups and the control group. Giacco et al.13 performed a moderate-quality randomized crossover study in 15 healthy overweight/ obese (BMI, 27.4 6 3.0 kg/m2) Italian men (n ¼ 12) and women (n ¼ 3). After a 2-week run-in period, the subjects were randomly assigned to follow 2 isocaloric diets for 3 weeks each. The subjects were advised not to modify their habitual intake of nongrain foods (meats, dairy products, eggs, fish, fruits, and vegetables) during the study. The only difference between the 2 diets was the inclusion of a fixed amount of whole-wheat (ie, wholegrain) foods or refined-wheat foods (control) as the main carbohydrate source at all meals. Both whole grains and refined grains were provided to the subjects. Compliance with the diets was evaluated using a 7-day food record at the start of the study, during the study, and at the end of the study. The subjects’ compliance with both diets was good. There was no significant difference in fasting blood glucose or insulin resistance (calculated by HOMA) between the whole-grain and refined-grain groups. Rave et al.24 conducted a moderate-quality randomized crossover study in 31 obese (BMI, 33.9 6 2.7 kg/m2) German men (n ¼ 13) and women (n ¼ 18) with elevated fasting blood glucose levels but without a diagnosis of type 2 diabetes. The participants in the whole-grain group consumed a diet containing whole-grain double-fermented wheat for 4 weeks, and those in the control group consumed a diet containing a nutrient-dense, high-fiber meal-replacement product that contained no whole grains (the reference meal), also for 4 weeks. The whole-grain group replaced at least 2 daily meals with either the double-fermented wheat or the reference meal, with the target consumption being 200 g of the assigned product per day. Both the whole-grain and the reference meals were provided in a powder form and were prepared in portions equivalent in calorie content. Subjects in the whole-grain group were instructed to dissolve the whole-grain Nutrition ReviewsV Vol. 74(10):601–611 R Nutrition ReviewsV Vol. 74(10):601–611 R 605 Study design 4-wk randomized, crossover Rave et al. (2007)24 12-wk randomized, parallel Study population 30 overweight/obese men and women at risk of type 2 diabetes in Sweden 316 overweight and obese men and women in the UK; 81–85 in each intervention group and 100 in control group 15 healthy normal-weight/ overweight/obese men and women in Italy 31 obese men and women at risk of type 2 diabetes in Germany 43 normal-weight/overweight/moderately obese men and women in the USA 206 normal-weight/overweight/moderately obese men and women in the UK Abbreviations: NA, not available; , no effect at P < 0.05. Tighe et al. (2010)100 Saltzman et al. (2001)26 6-wk randomized, parallel 3-wk randomized, crossover Giacco et al. (2010)13 Brownlee et al. (2010)12 16-wk randomized, controlled, parallel Andersson et al. (2007)9 6-wk randomized, crossover Reference Table 1 Summary of intervention studies on whole grains and type 2 diabetes 70–80 g of whole-wheat bread plus 30–40 g of whole-grain cereals; or 1 serving of whole-wheat food and 2 servings of oats (no amount given) 45 g/1000 kcal rolled oats 200 g/d (double-fermented whole wheat) NA 60–120 g/d 112 g/d Whole-grain intake level Beneficial effect after adjustment for body-weight loss (P < 0.049) Insulin resistance Fasting blood glucose Results NA NA NA NA NA NA Oral glucose tolerance test powder in water, skim milk, or yogurt, while those in the reference-meal group were instructed to dissolve the powder in skim milk. All subjects were interviewed by a dietitian during the first, second, and third week of the study to assess compliance with the study diet, changes in body weight, and any potential adverse events. In addition, they recorded their daily food intake each day, using a standardized questionnaire. All participants adhered to their prescribed diets. After 4 weeks, each group showed a loss in body weight, lower fasting blood glucose levels, and improved insulin resistance (calculated by HOMA), but there were no significant differences between the groups. After statistical adjustment for body weight reduction, insulin resistance was significantly reduced in the whole-grain group compared with the control group (P < 0.049). Notably, the powdered, double-fermented whole-grain product used in this study was significantly different from the whole-grain products generally available for purchase in the United States.101 The study by Saltzman et al.26 was a moderatequality 8-week parallel intervention that included 43 healthy US adults with a BMI of 26.4 6 3.3 kg/m2. The 8-week protocol was divided into a 2-week weightmaintenance phase (phase 1), during which habitual diets were consumed, followed by a 6-week weight-loss phase (phase 2). During phase 2, the subjects consumed 1 of 2 reduced-calorie diets (weight-maintenance calories minus 1000 kcal/d). The intervention group (n ¼ 22) received a diet that included 45 g of rolled whole-grain oats (roughly equivalent to 1.5 servings of oatmeal) per 1000 kcal. The control group (n ¼ 21) received a diet equivalent in calories to the intervention group diet, but without oats. The 2 diets were matched for insoluble fiber, fat, protein, and carbohydrate content. All foods and calorie-containing beverages were provided to the subjects, who were required to eat at least 4 meals per week in the metabolic research unit, with the other meals provided as take-out. The subjects’ compliance with both diets was good. There was no significant difference in fasting blood glucose or insulin resistance (calculated by HOMA) between the intervention and control groups. Tighe et al.100 conducted a high-quality, randomized, parallel controlled hypocaloric 12-week intervention study in the United Kingdom in men (n ¼ 102) and women (n ¼ 104) with a BMI (kg/m2) between 18.5 and 35. After a 4-week run-in period on a refined-grain diet, subjects (stratified by age, sex, and BMI) were randomly assigned to 1 of 3 groups. The first group (control) (n ¼ 63) consumed a diet that included refined cereals and white bread. The second group (n ¼ 73) replaced 3 servings of refined grains with whole-wheat foods (70–80 g of whole-grain bread plus 30–40 g of 606 whole-grain cereal), and the third group (n ¼ 70) replaced 3 servings of refined grains with 1 serving of whole-wheat food plus 2 servings of whole-grain oats. All refined and whole-grain products were provided to the subjects. Compliance was determined by dietary assessment on 3 occasions during the intervention period. The subjects’ compliance with the diets was good. There was no significant difference in fasting blood glucose levels or insulin resistance (calculated by HOMA) between the whole-grain groups and the control group. EVALUATION OF OBSERVATIONAL STUDIES The FDA reviewed 40 articles27–49,83–99 reporting on 41 observational studies. The articles contained a total of 44 analyses evaluating the association between wholegrain intake and risk of type 2 diabetes. Two of these articles examined more than 1 observational study and contained more than 1 analysis. Specifically, the publication by de Munter et al.27 evaluated the association between whole-grain consumption and incidence of type 2 diabetes on the basis of data from 2 prospective cohort studies, the NHS I and the NHS II. The authors analyzed data for whole-grain consumption and its association with type 2 diabetes separately for each of these studies. Sun et al.45 analyzed data from 3 prospective cohort studies, ie, the 2 reported by de Munter et al.27 (NHS I and NHS II) and the HPFS, to evaluate the association between brown rice intake and risk of type 2 diabetes. They also analyzed the association between whole-grain intake and risk of type 2 diabetes using data from the HPFS. In total, the FDA evaluated 44 individual analyses from the 40 articles on 41 observational studies. Scientific conclusions could not be drawn from 38 of the articles on observational studies 28–44,46–49,83–99 for 1 or more of the following reasons: (1) the whole grains measured in these studies were not consistent with the FDA’s definition of whole grain2; (2) the study report failed to specify what foods were considered to be whole grain; or (3) the studies evaluated dietary patterns and not only whole grains. In the majority of these studies, bran, germ, and/or dietary fiber added separately to food was considered part of the whole-grain food group. As mentioned above, a substance containing only parts (eg, bran, germ, or dietary fiber) of the caryopsis of a cereal grain is not whole grain because it does not consist of the intact, ground, cracked, or flaked caryopsis and does not have anatomical components present in the same relative proportions as they exist in the intact caryopsis. Therefore, the FDA could not draw scientific conclusions about the association between whole-grain intake and risk of type 2 diabetes from these 38 studies. Nutrition ReviewsV Vol. 74(10):601–611 R Table 2 Summary of observational studies on whole grains and type 2 diabetes Reference de Munter et al. (2007) Sun et al. (2010)45 27 Study design Study population 2 cohort studies: NHS I and NHS II; whole grains; validated FFQ NHS I – 18-y follow-up Healthy women in the USA with no history of disease Participants ¼ 73 327 Overall cases ¼ 4747 NHS II – 12-y follow-up Participants ¼ 88 410 Overall cases ¼ 1739 Cohort study – HPFS Healthy men in the USA with no history of disease Participants ¼ 39 765 Overall cases ¼ 2648 Whole grains; validated FFQ; 20-y follow-up Sun et al. (2010)45 3 cohort studies (HPFS, NHS I, NHS II); brown rice; validated FFQ HPFS: 20-y follow-up Healthy men and women in the USA Participants ¼ 39 765 men Overall cases ¼ 2648 NHS I: 22-y-follow-up Participants ¼ 69 120 women Overall cases ¼ 5500 NHS II: 14-y follow-up Participants ¼ 88 343 women Overall cases ¼ 2359 Intake level Median intake Q1 (reference intake) ¼ 3.7 g Q2 ¼ 8.4 g Q3 ¼ 13.2 ga Q4 ¼ 19.5 ga Q5 ¼ 31.2 ga Q1 ¼ 6.2 g Q2 ¼ 12.6 g Q3 ¼ 18.6 g Q4 ¼ 26.1 ga Q5 ¼ 39.9 g Median intake Q1 ¼ 5.1 g Q2 ¼ 12.6 ga Q3 ¼ 20.4 ga Q4 ¼ 29.9 ga Q5 ¼ 47.1 ga 1 serving/wk to 1 serving/ 1 serving mo (0.6 g) 2 servings/wk (3.5 g) 1 serving/wk to 1 serving/ 1 serving mo (0.6 g)b 2 servings/wk (3.5 g)b 1 serving/wk to 1 serving/ 1 serving mo (0.6 g) 2 servings/wk (3.5 g) Abbreviations: FFQ, food frequency questionnaire; HPFS, Health Professionals Follow-up Study; NHS, Nurses’ Health Study; Q, quintile. effect at each quintile compared with Q1 (reference intake). Beneficial effect compared with <1 serving per month. a Beneficial b There were 6 analyses of 3 observational studies that evaluated the association between whole-grain intake and risk of type 2 diabetes (de Munter et al.,27 examining NHS I and NHS II, and Sun et al.,45 examining HPFS, NHS I, and NHS II) from which scientific conclusions could be drawn (Table 2). As mentioned above, the HPFS study reported by Sun et al.45 included analyses of 2 diet–disease associations: the association between intake of whole grains, which include brown rice, and risk of type 2 diabetes, and the association between intake of brown rice and risk of type 2 diabetes. de Munter et al.27 analyzed data from 2 high-quality prospective cohort studies (NHS I and NHS II). The NHS I followed 73 327 women (aged 37–65 years) and the NHS II 88 410 women (aged 26–46 years). About 4747 (NHS 1) and 1739 (NHS II) cases of type 2 diabetes were identified in these studies. Whole grains included both intact and pulverized forms containing the expected proportion of bran, germ, and endosperm for the particular type of grain. Whole-grain intake from all sources was assessed using a validated food frequency questionnaire. In the NHS I, after adjustment for appropriate confounders, including BMI, higher whole-grain intake was associated with a significant Nutrition ReviewsV Vol. 74(10):601–611 R reduction in risk of type 2 diabetes for the 3 highest quintiles (Q) of intake (median whole-grain intake, 13.2 g/d or higher). Specifically, relative risk (RR) and 95% confidence intervals (95%CIs) were 0.84 (95%CI, 0.77–0.92), 0.79 (95%CI, 0.72–0.87), and 0.75 (95%CI, 0.68–0.83) in Q3 (median whole-grain intake, 13.2 g/d), Q4 (19.5 g/d), and Q5 (31.2 g/d), respectively, when compared with Q1 (3.7 g/ d). The RR and 95%CI in Q2 (median whole-grain intake, 8.4 g/d), which did not show a significantly reduced risk of type 2 diabetes compared with Q1, were 0.92 and 0.84– 1.00. In the NHS II, after adjustment for all relevant confounders, including BMI, a significant association was found between whole-grain intake and reduced risk of type 2 diabetes in Q4 (median whole-grain intake, 26.1 g/ d) compared with Q1 (6.2 g/d) (RR ¼ 0.81; 95%CI, 0.69– 0.95). However, no significant association was observed in Q5 (39.9 g/d) compared with Q1 (RR ¼ 0.86; 95%CI, 0.72– 1.02). Similarly, no significant association was observed in Q2 (12.6 g/d) (RR ¼ 0.94; 95%CI, 0.82–1.08) or Q3 (18.6 g/ d) (RR ¼ 0.90; 95%CI, 0.78–1.08) compared with Q1. Thus, unlike the NHS I, the NHS II did not indicate a consistent dose–response association between whole-grain intake and reduction in risk of type 2 diabetes. 607 Sun et al.45 analyzed data from the HPFS, the NHS I, and the NHS II to evaluate the association between consumption of brown rice (a whole grain) and incidence of type 2 diabetes. These studies were of high quality and followed 39 675 men (aged 32–87 years) from the HPFS, 69 120 women (aged 37–65 years) from the NHS I, and 88 343 women (aged 26–45 years) from the NHS II. The numbers of type 2 diabetes cases in these studies were 2648 (HPFS), 5500 (NHS I), and 2359 (NHS II), respectively. In the NHS I, after adjustment for appropriate confounders, there was a significantly reduced risk of type 2 diabetes for those who consumed from 1 serving per month to 1 serving per week of brown rice compared with those at the lowest level of intake (<1 serving/month) (RR ¼ 0.92; 95%CI, 0.87–0.98) as well as for those who consumed 2 or more servings per week compared with those at the lowest level of intake (RR ¼ 0.83; 95%CI, 0.72–0.96). There was no significant association between brown rice consumption and incidence of type 2 diabetes in the NHS II or the HPFS. Sun et al.45 also analyzed intake of all whole grains using the same definition as de Munter et al.27 After adjustment for appropriate confounders, there was a significant association between quintiles of whole-grain intake and reduced risk of type 2 diabetes in Q2 (12.6 g/d) (RR ¼ 0.82; 95%CI, 0.73–0.92], Q3 (20.4 g/d) (RR ¼ 0.86; 95%CI, 0.77–0.97), Q4 (29.9 g/d) (RR ¼ 0.78; 95%CI, 0.69–0.88), and Q5 (47.1 g/d) (RR ¼ 0.72; 95%CI, 0.63–0.83) compared with Q1 (5.1 g/d). STRENGTH OF THE SCIENTIFIC EVIDENCE The evidence for a relationship between whole-grain intake and type 2 diabetes risk was derived from 6 intervention studies9,12,13,24,26,100 and 2 publications27,45 that together contain a total of 6 analyses of 3 prospective cohort studies. Of the 6 intervention studies evaluated, 5 reported no significant relationship between whole-grain intake and incidence of type 2 diabetes.9,12,13,26,100 These 5 studies were of moderate or high quality and consisted of randomized controlled trials that examined types of whole-grain products (eg, whole-wheat bread, oatmeal) typically purchased by US consumers.101 The studies by Brownlee et al.12 and Tighe et al.100 were both of high quality and had the longest study durations (16 weeks and 12 weeks, respectively) and the largest number of subjects. Brownlee et al.12 had 266 subjects, with about 80 to 100 in each of 3 groups, while Tighe et al.100 had 206 subjects, with about 70 per group. Both studies included both men and women. The study by Rave et al.24 was a 6-week, moderatequality, randomized controlled weight-loss study. After 608 adjustment for the amount of weight loss, there was no significant reduction in fasting blood glucose in the whole-grain group compared with the control group, but a significant improvement in insulin resistance was observed in the whole-grain group compared with the control group (P < 0.049). There are serious doubts about this study’s applicability to whole-grain consumption in the general US population. The whole-grain product in this study was a dry powder derived from double-fermented wheat and was consumed in large quantities (total of 200 g/d) as a meal replacement. This product is significantly different from the whole-grain products available to consumers for purchase in the US marketplace. Commonly available whole-grain products in the US marketplace are neither double fermented nor in powder form.101 Moreover, since the study subjects followed a diet designed to cause weight loss, the study does not rule out the possibility that the benefit would only be observed during a period of caloric reduction, such as dieting, and not when whole grains are consumed as part of a weight-maintenance or highcalorie diet. The results of the 6 analyses of the 3 observational studies from which scientific conclusions could be drawn were mixed. All 3 prospective cohort studies showed a significant association between whole-grain intake and reduced risk of type 2 diabetes (NHS I, NHS II, HPFS).27,45 However, when Sun et al.45 analyzed the association between brown rice consumption and incidence of type 2 diabetes in the same 3 prospective cohort studies (NHS I, NHS II, and HPFS), the only study that showed a significant association between brown rice intake and reduced risk of type 2 diabetes was the NHS I. No association between brown rice intake and risk of type 2 diabetes was found in the NHS II or the HPFS. Thus, the findings of the brown rice studies were not consistent. In general, results from large, well-designed, randomized controlled intervention studies provide the strongest evidence for the claimed effect, regardless of existing observational studies on the same relationship. Intervention studies are designed to avoid selection bias and avoid findings that are due to chance or other confounders of disease.102 Although the evaluation of substance/disease relationships often involves both intervention and observational studies, observational studies generally cannot be used to rule out the findings from more reliable intervention studies.102 One intervention study would not be sufficient to rule out consistent findings of observational studies. However, when several randomized controlled intervention studies are consistent in showing or not showing a substance/disease relationship, they take precedence over the findings of any number of observational studies.3,103 This is Nutrition ReviewsV Vol. 74(10):601–611 R because intervention studies are designed and controlled to test whether there is evidence of a cause-andeffect relationship between a substance and a reduced risk of a disease, whereas observational studies are only able to identify possible associations. There are numerous examples – such as vitamin E and cardiovascular disease, and b-carotene and lung cancer – for which associations identified in observational studies have been publicized. However, when randomized controlled intervention studies were later conducted to test these possible associations, the intervention studies found no evidence to support the relationships.3,104 Consistency of findings among similar and different study designs is important for evaluating the strength of the scientific evidence.3,105 The majority of the intervention studies included in FDA’s evaluation did not show a significant relationship between whole-grain consumption and reduced risk of type 2 diabetes. Only 1 intervention study24 showed a significant relationship. It is doubtful, however, whether the results of that study apply to the general US population because the powdered, double-fermented wheat product tested in that study is markedly different in composition and conditions of use from whole-grain products typically used in the United States. Further, the reported individual findings of Rave et al.24 have not been replicated in any other intervention studies, and replication of scientific findings is important in order to substantiate results.3,106 CONCLUSION On the basis of the agency’s evidence-based review, there are 4 analyses of 3 observational studies and 1 intervention study supporting an association between consumption of whole grains and reduced risk of type 2 diabetes, while 5 intervention studies and 2 additional analyses of observational studies found no evidence of such a relationship. Among the observational studies, the results of analyses examining intake of whole grains of all types were generally consistent, with 3 analyses finding a significant association between whole-grain consumption and reduced risk of type 2 diabetes at some level of intake. However, of the 3 analyses that were limited to brown rice, only 1 found a significant association between brown rice intake and reduced risk of type 2 diabetes. The sole intervention study24 suggesting a causal relationship is not well suited to assess whether whole-grain foods commonly consumed in the United States reduce the risk of type 2 diabetes, as it examined the effects of a whole-grain product in an unusual form (powdered mix containing double-fermented whole wheat), at a very high intake level (200 g/d), and under atypical conditions of use (meal replacement to be mixed with a liquid and substituted for 2 of the day’s 3 meals). Moreover, the results Nutrition ReviewsV Vol. 74(10):601–611 R of relevant studies are not consistent within or across study types, and the prospective cohort studies suggesting a link between whole-grain intake and reduced risk of type 2 diabetes are undermined by several randomized controlled intervention studies that measured surrogate endpoints of type 2 diabetes risk and found that whole-grain intake had no effect. On the basis of its scientific review, the FDA, on September, 2013, issued a letter of enforcement discretion for the use of the following claim: “Whole grains may reduce the risk of type 2 diabetes, although the FDA has concluded that there is very limited scientific evidence for this claim.”107 Since the FDA issued the letter of enforcement discretion on whole grains and risk of type 2 diabetes, several systematic reviews or meta-analyses on this topic have been published. As noted above, the FDA does not rely on published systematic reviews and/or metaanalyses but instead conducts evidence-based reviews of the scientific data. Two individual cohort studies have been published since the completion of the FDA review. In one,108 it was not clear how whole grain was defined. In the other, the impact of whole grains on the progression of normal glucose tolerance to type 2 diabetes was not significant in either men (OR ¼ 0.72; 95%CI, 0.44– 1.16) or women (OR ¼ 0.68; 95%CI, 0.35–1.33).109 The FDA has not conducted a detailed review of these studies using the evidence-based review system. Nevertheless, a preliminary appraisal indicates that the findings of these studies do not appear to contradict the conclusions of the earlier review supporting the issuance of the letter of enforcement discretion.107 Acknowledgments Declaration of interest. The authors have no relevant interests to declare. REFERENCES 1. 2. 3. 4. 5. 6. 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