Adverse Effects: Consideration of Chronic Disease Endpoints and Beyond Amanda MacFarlane, PhD. Nutrition Research Division, Health Canada, Ottawa, ON

Transcription

1 Adverse Effects: Consideration of Chronic Disease Endpoints and Beyond Amanda MacFarlane, PhD Nutrition Research Division, Health Canada, Ottawa, ON

2 Adverse effects can be described as: Biochemical and physiological responses that lead to structural or functional alterations that impair/compromise health Arising at any stage of growth, development, and life Permanent or reversible Reductions in the capacity of an organism to respond to additional insults, are also considered adverse. Chronic diseases can be described as encompassing any or all of these characteristics 2

3 DRI values based on: Data from apparently healthy populations Relationships between nutrient intakes and indicators of: Adequacy Current DRI Framework Adverse effects Chronic disease risk reduction where sufficient data for efficacy and safety exist

4 Approach to Setting DRI Values U shaped curve for risk Estimate Average Requirement (EAR) Recommended Dietary Allowance (RDA) Tolerable Upper Intake Level (UL) 4

5 DRI Values In general, DRI values only set for adequacy and adverse effects of high intakes Each time a chronic disease endpoint was used, a limitation of the application of the classic DRI approach to CD was highlighted Short answer: It was hard! 5

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7 Classic EAR/RDA/UL approach Classic EAR/RDA/UL approach depends on: Essentiality of the substance Relevant population Threshold for adequacy and adverse effects Applicability of U shaped risk curve Nature of the evidence dictates nature of the risk These don t always apply to nutrient chronic disease relationships 7

8 Assumption: Relevant population All persons, all life stage groups 100% of population affected by inadequate intakes Eg. Vitamin D and bone health IOM,

9 Assumption: Relevant population Chronic Disease: Not all persons, not all life stage groups Often significantly <50% of population affected by the CD Eg. Diabetes by age e.htm 9

10 Assumption: Threshold for adequacy Threshold effect/inflection point between inadequate and adequate intakes 10

11 Assumption: Threshold for upper intake level Highest average daily intake level likely to pose no risk of adverse health effects for nearly all people Nutrient adverse effects assumed to have an inflection point Intakes above the UL increases the risk of adverse effects 11

12 Assumption: Threshold for benefit/risk Nutrient CD relationships often lack an inflection point Eg. Saturated fats and LDL cholesterol Also no benefit : Keep intakes as low as possible while consuming a nutritionally adequate diet 12

13 Assumption: Interval between intakes associated with benefit and harm 13

14 Sodium and blood pressure no threshold and benefit overlaps harm Relationship is linear at all doses NO UPPER THRESHOLD AI (1.5 g) based on adequacy for other nutrients and sweat losses UL (2.3 g) based on the next higher dose in trials 14

15 Assumption: Nature of the evidence Establishing causality and dose response RCT Intervention trials Metabolic/balance studies Depletion/repletion studies 3 doses (D R) Meta-An SR Data quality Modified from George Wells 15

16 Assumption: Nature of the evidence Nutrient Chronic Disease evidence mostly observational or associational Establishment of causality and/or dose response in absence of RCTs Meta-An SR Data quality 16

17 Nature of available evidence also dictates: Nature of risk: absolute vs relative Biomarkers and indicators of disease used to establish relationship Inherent errors/unknowns associated with study type Confounding and selection bias Self reported intake Multifactorial nature of chronic disease 17

18 Assumption: Nature of risk Risk for diseases of deficiency/adverse effects defined as absolute At high and low intakes, there would be 0 or 100% risk 18

19 Assumption: Nature of risk Risk for chronic diseases is defined as relative risk Intake of most nutrients alters risk of disease by small amount in relative terms (eg. <10%) No one in a population is at 0 or 100% risk rather they are at higher or lower risk compared to a baseline Intake with greatest effect at tail(s) of intake distribution Highest or lowest intakes 19

20 Relative risk: Fibre and coronary heart disease BMJ 2013;347:f6879 Fibre AI based on median intake to achieve lowest relative CHD risk Could other levels of risk reduction be acceptable? 20

21 Assumption: Biomarkers on causal pathway Direct observations of adverse outcomes due to low (EAR/RDA) or high (UL) intake of nutrient Indicators of status on the causal pathway for diseases of deficiency Serum folate, serum 25(OH)D, serum ferritin Exposure Indicators of exposure Clinical outcomes 21

22 Assumption: Biomarkers on causal pathway Nutrient CD often linked only by surrogate or intermediate outcomes Validated biomarkers are few and far between 22

23 Key takeaways The classic DRI approach works well for essential nutrients Allows for EAR/RDA and UL (generally) It does not work well for chronic disease endpoints Nature of chronic disease means the assumptions used to define EAR/UL do not always apply Nature of the available evidence differs significantly from that available for establishing essentiality/toxicity 23

24 Beginning to address the inclusion of chronic disease endpoints in future DRIs: Workshop: Options for Consideration of Chronic Disease Endpoints for Dietary Reference Intakes (DRIs) (March 2015) To critically evaluate key scientific issues involved in using chronic disease endpoints for setting DRIs To provide options for future decisions as to whether and/or how chronic disease endpoints can be incorporated into the setting of DRI values. 24

25 Thank you! The Development of DRIs : Lessons Learned and New Challenges: Workshop Summary Marla Sheffer and Christine Lewis Taylor Challenges with using chronic disease endpoints in setting dietary reference intakes. Paula Trumbo Nutrition Reviews Vol. 66(8): Workshop website: 11_2015.aspx 25