Applying the DRI Framework to Chronic Disease Endpoints

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1 Applying the DRI Framework to Chronic Disease Endpoints Paula R. Trumbo, Ph.D. U.S. Food and Drug Administration Institute of Medicine, Food and Nutrition Board Workshop Development of DRIs, : Lessons Learned and New Challenges September 18-20, 2007

2 How Should the Recommended Dietary Allowances Be Revised (IOM, 1994) One of three general conclusions: Reduction in risk of chronic disease is a concept that should be included in the formulation of future RDAs where sufficient data for efficacy and safety exist

3 Dietary Reference Intakes Standing Committee on the Scientific Evaluation of Dietary Reference Intakes Panels Ca, Vitamin D, Phosphorus, Mg, F Upper Reference Levels Subcommittee Folate, B 12, Other B Vitamins, Choline Vitamins C and E, Se, ß-carotene and Other Carotenoids Uses of DRIs Subcommittee Vitamins A and K, B, Cr, Cu, Fe, I 2, Mn, Mo, Ni, Si, V, Zn Energy and Macronutrients Electrolytes, Water Other Food Components Alcohol

4 Guiding Principles for Setting Recommended Intake Levels Evaluate the evidence on chronic disease risk in addition to the evidence on daily requirements - 5 of 34 nutrients based on chronic disease

5 Guiding Principles for Setting Recommended Intake Levels Try to set an EAR/RDA (rather than an AI) - None of these 5 nutrients were assigned an EAR/RDA

6 Recommended Intake Levels Based on Risk Reduction of Chronic Disease Calcium & Vitamin D (AI) Fluoride (AI) Fiber (AI) Potassium (AI) Osteoporosis /fractures, as well as other endpoints Dental caries Coronary heart disease Salt sensitivity/ kidney stones/bp

7 Could have EARs been set based on chronic disease?

8 Estimated Average Requirement A average daily nutrient intake level that is estimated to meet the requirement* of half the healthy individuals in a life stage and gender group *Defined by the nutrient-specific indicator or criterion of adequacy

9 Estimated Average Requirement

10 EAR Based on Essentiality Nutrient-specific the risk of inadequacy for a specific nutrient Using a nutrient-specific indicators Balance (molybdenum) Factorial (iron, zinc) Biomarkers of status (copper, vitamin E) Turnover (iodine, carbohydrate) All individuals are at risk of inadequacy of an essential nutrient

11 Recommended Intake Levels Based on Risk Reduction of Chronic Disease Calcium & Vitamin D (AI) Fluoride (AI) Fiber (AI) Potassium (AI) Osteoporosis /fractures, as well as other endpoints Dental caries Coronary heart disease Salt sensitivity/ kidney stones/bp

12 Potassium & Salt Sensitivity

13 Risk of Inadequacy vs Risk of Chronic Disease

14 Estimated Average Requirement & Chronic Disease EAR = Nutrient Intake level to reduce the risk of chronic disease in half the healthy individuals in a life stage and gender group Absolute Risk Reduction: Absolute Risk (probability of getting a disease over a certain time period (e.g., 1 in 4 are at risk of.) Relative Risk Reduction (risk factor, e.g., nutrient)

15 Absolute Risk Osteoporosis the prevalence of osteoporosis among postmenopausal women in the United States is 21% for Caucasian and Asian, 16% in Hispanic, and 10% in African American women. (IOM, 1997; Looker et al., 1995) Prevalence of osteoporosis of the hip in women 65-74, 75-84, and 85+ years is 19%, 32%, 50%, respectively (SG report, 2004) Coronary Heart Disease (CDC; Ford et al., 2004) For adults years, 10-year risk of CHD is <10% for 82% of population Ten-year risk of CHD is > 20% for 22% of men years Kidney Stones (NIDDK) Prevalence is approximately 5%

16 Risk Reduction Chronic diseases are not nutrient-specific Chronic diseases are multi-factorial with other factors, such as genetics, environment, lifestyle and other nutrients, contributing to risk Unlike the effectiveness of reducing the risk of a nutrient deficiency, risk reduction of most chronic diseases by diet is limited

17 Risk Reduction Calcium and Osteoporosis (IOM, 1997) Osteoporosis results from complex interactions among genetic, dietary and other environmental factors Rejected observational data on fracture risk due to the influence of confounding factors Vitamin D and Osteoporosis (IOM, 1997) Could not account for the contribution of sunlight exposure which is affected by a wide variety of factors

18 Risk Reduction Dental Caries (IOM, 2002) Caries occurrence is influenced by frequency of meals and snacks, sugar content of foods, oral hygiene, water fluoridation, fluoride supplementation and toothpaste Fiber and CHD (IOM, 2002) 3 prospective cohorts Relative risk reduction ( ) Potassium and Kidney Stones (IOM, 2005) 3 prospective cohorts Relative risk reduction ( )

19 Intervention Data: Fat/Carbohydrate and Risk Biomarkers of CVD

20 Chronic Disease and Setting an EAR/RDA Not applying a nutrient-specific indicator Unlike specific nutrient deficiencies that can occur in all individuals, the absolute risk of most chronic diseases is a portion of the population Increased/decreased nutrient intake can yield significant reductions in the relative risk of a disease, however, Relative risk reduction of most chronic diseases by a single nutrient is limited Therefore, the definition of an EAR does not allow for the use of chronic disease risk reduction in setting intake levels

21 IOM, 1994 Page 15, If reduction of risk of chronic disease is to become a criterion in the development of future RDAs, many questions must be faced. Some of them being: How can concerns regarding potential interactions among nutrients be addressed? Should levels of nutrient intake be expressed in terms of numerical ranges [AMDR], in terms of food patterns, or in some other way? Page 32, Some commenters at the 1993 meeting argued that the RDAs should remain distinct from dietary guidelines from reducing risk of chronic disease

22 Adequate Intake and Chronic Disease Based on observed or experimentally determined estimates of intake - observational studies Expected to meet or exceed the amount needed to maintain a defined nutritional state or criterion of adequacy in essentially all members of a specific healthy population. - expect the recommended intake level based on chronic disease to be greater than a recommended intake level based on the daily requirement for most essential nutrients

23 If chronic disease endpoints continue to be used in setting a recommended intake level, one or more of the following could be considered: Continue to set Adequate Intakes Based on clinical/observational data Continue to set AMDRs for macronutrients (lower range) Based on clinical/observational and dietary intake data Develop new criteria/dri that provides a prescriptive way in setting recommendations based on chronic disease endpoints

24 Guiding Principles for Setting Tolerable Upper Intake Levels Set a UL based on a NOAEL UL is the highest intake level likely to pose no risk Less uncertainty Otherwise, set a UL based on a LOAEL

25 Risk of inadequacy EAR RDA AI UL NOAEL LOAEL Risk of excess Observed level of intake Increase

26 Nutrients without a NOAEL There was evidence to suggest that no observed adverse effects occurred at lower intake levels (a threshold exists), however, the exact NOAEL could not be identified --- essential nutrients OR There was evidence to demonstrate no threshold effect --- nonessential nutrients

27 Essential Nutrients without a NOAEL A UL could be set if sufficient data were available for identifying a LOAEL Only one UL was set based on a chronic disease endpoint - sodium and blood pressure (surrogate endpoint for CVD)

28 Sodium Intake and Blood Pressure

29 Sodium and Blood Pressure A NOAEL was not identified because of a lack of a threshold --- it was not known if blood pressure would continue to drop below the lowest sodium intake level (50 mmol/day) AND the AI was set at 60 mmol/day (factorial) LOAEL = 100 mmol/day (2.3 g/day)

30 Non-essential Nutrients without a NOAEL There was no observed threshold effect using risk biomarkers of CVD Trans fat LDL/HDL cholesterol Saturated fat LDL and LDL/HDL cholesterol Cholesterol total cholesterol

31 Saturated Fatty Acid Intake & Change in LDL Cholesterol Change in LDL Cholesterol (mg/dl) Mensink and Katan (1992) Hegsted et al. (1993) Clarke et al. (1997) Mean Saturated Fatty Acids (% energy)

32 Trans Fatty Acid and Saturated Fatty Acid Intake and Increase in LDL:HDL Cholesterol Ratio

33 Increasing Intake of Cholesterol and Serum Total Cholesterol 3 Defined Diets (Data from Table 1) 2.5 Self-Selected Diets (Data from Table 2) Linear (Defined Diets (Data from Table 1)) Change in Serum TC (mmol/l) Linear (Self-Selected Diets (Data from Table 2)) y = x R 2 = y = x R 2 = Change in Dietary Cholesterol (mg/d)

34 Saturated Fat, Trans Fat and Cholesterol And CVD Risk Biomarkers The relationships were a continuum The lowest intake levels approached zero or near zero for percent change in the risk biomarkers

35 No UL Set for Saturated Fat, Trans Fat and Cholesterol Any intake level > zero resulted in an increased risk of heart disease Difficult to avoid foods that contain these macronutrients Significant changes in patterns of dietary intake

36 Possible Approach to Setting Maximum Intake Levels for Nonessential Nutrients without a Threshold Set a maximum intake level similar to the approach used to set upper range of an AMDR Clinical/observational data Dietary data Menu modeling -Lowest amount to meet essential nutrients (saturated fat) Survey data analysis of varying intake levels of a nutrient on the intake of other nutrients

DRIs. Dietary Reference Intakes. IOM DRI Research Synthesis Workshop June 7-8, Approach and Framework of the DRIs

DRIs. Dietary Reference Intakes. IOM DRI Research Synthesis Workshop June 7-8, Approach and Framework of the DRIs Approach and Framework of the DRIs John W. Erdman Jr., Ph.D. Dept of Food Science and Human Nutrition University of Illinois at Urbana-Champaign DRIs Food and Nutrition Board 119-02 U.S. Nutrient Recommendations