1.Sugars and Health Controversies: What Does the Science Say? A Sponsored Satellite Program held in conjunction with the American Society for Nutritions Scientific Sessions at Experimental Biology 2014 April 26, 2014 Moderator: James Rippe, MD Panelits: Mei Chung, PhD, MPH, exploring the latest science on sugars John Sievenpiper, MD, PhD, talking about sugars and their associated health outcomes Roger Clemens, DrPH, discussing related public policy implications Sponsored by the Corn Refiners Association SWEETENER STUDIES.com A SCIENTIFIC EXAMINATION OF HFCS & OTHER SWEETENERS

2. James M. Rippe, M.D. Professor, Biomedical Sciences University of Central Florida Founder and Director Rippe Lifestyle Medicine American Society of Nutrition Satellite Symposium Experimental Biology April 26, 2014 2 3. Rippe Lifestyle Institute (RLI) has received unrestricted grant funding to conduct research trials and/or received consulting fees from a variety of companies, organizations, publishers or trade associations that utilize, market or publish information about fructose, high fructose corn syrup or sucrose and hence, have an ongoing interest in the metabolism and health effect of these sugars. 3 4. OBJECTIVES Explore controversies related to the metabolism and health effects of sugars. Review modern science related to these issues with particular reference to systematic reviews, meta-analyses and randomized controlled trials. Discuss how scientific understandings interact with public policy. Suggest further areas of needed research. 4 5. CONTROVERSIES/QUESTIONS Are there differences in metabolism and health effects between fructose, high fructose corn syrup (HFCS) and sucrose? Do fructose containing sugars contribute significantly to conditions such as Non Alcoholic Fatty Liver Disease (NAFLD), Obesity, Diabetes, Cardiovascular Disease (CVD), the Metabolic Syndrome, Dyslipidemias or elevated Blood Pressure? Do fructose containing sugars react differently in the brain than glucose? If so, is that relevant to appetite, food consumption, weight gain and obesity? 5 6. CONTROVERSIES/QUESTIONS (CONTINUED) What is the appropriate upper limit of consumption of sugars? Are public policy recommendations to limit consumption of sugars through such mechanisms as taxation or limiting portion sizes based on sound science and/or likely to succeed? What directions should future research take? 6 7. RLI has conducted a series of randomized controlled trials comparing HFCS, sucrose, fructose, and glucose at dosages up to the 90th percentile population consumption level of fructose exploring metabolism and health related parameters in the following areas: Energy regulating hormones Appetite Weight Body composition Risk factors for CVD Risk factors for diabetes Risk factors for the metabolic syndrome Lipids Blood pressure Liver fat accumulation Muscle fat accumulation Brain responses (hypothalamus and reward pathways) Findings to date at normally consumed levels of sugars (up to the 90th percentile population consumption level of fructose) No differences among the sugars No adverse health consequences 7 8. SUMMARY STATEMENTS 8 9. Bray GA, Popkin BM. Dietary sugar and body weight: Have we reached a crisis in the epidemic of obesity and diabetes?: Health be damned! Pour on the sugar. Diabetes Care. 2014;37:950-956 Kahn R, Sievenpiper JL. Dietary sugar and body weight: Have we reached a crisis in the epidemic of obesity and diabetes?: We have, but the pox on sugar is overwrought and overworked. Diabetes Care. 2014;37:957-962 van Buul VJ, Tappy L, Brouns FJ. Misconceptions about fructose-containing sugars and their role in the obesity epidemic. Nutr Res Rev. 2014:1-12 9 10. 10 11. TODAYS SPEAKERS Mei Chung, Ph.D., MPH Adjunct Professor Friedman School of Nutrition Science and Policy Do Fructose Containing Sugars at Current Levels Lead to Non-Alcoholic Fatty Liver Disease (NAFLD) and Associated Health Sequalae Roger Clemens, Dr PH Adjunct Professor Pharmacology and Pharmaceutical Sciences Department of Pharmacy, USC Added Sugars and Health: Industry Perspective John L. Sievenpiper, M.D., Ph.D. Knowledge Synthesis Lead Toronto 3D Knowledge and Clinical Trials Unit Clinical Nutrition and Risk Factor Modification Center Does Consumption of Fructose containing sugars lead to adverse health consequences: Results of recent systematic reviews and meta-analyses 11 12. Fructose, high fructose corn syrup, sucrose, and nonalcoholic fatty liver disease or indices of liver health April 26, 2014 Mei Chung, PhD, MPH Research Assistant Professor Dept. of Public Health & Community Medicine Tufts University School of Medicine 12 13. Disclosures for Mei Chung AFFILIATION/FINANCIAL INTERESTS CORPORATE ORGANIZATION Grants/Research Support: None Scientific Advisory Board/Consultant: None Speakers Bureau: None Stock Shareholder: None Other None 14. Objectives A systematic review of published literature What is the effect of different levels and forms of dietary fructose on the incidence or prevalence of NAFLD and on indices of liver health in humans? Future research needs assessment To prioritize future research needs regarding sugars and health. 14 15. Background 15 Natural history of the disease is not well understood Nonalcoholic fatty liver disease (NAFLD) now refers to a spectrum of pathologic disorders Hepatic steatosis: deposition of triglycerides as lipid droplets in the cytoplasm of hepatocytes NASH (nonalcoholic steatohepatitis): presence of hepatocyte injury (hepatocyte ballooning and cell death), an inflammatory infiltrate, and/or collagen deposition (fibrosis) 16. Background - continued Fructose hypothesis causative relationship between the increased prevalence of NAFLD and related disorders and intake of sweeteners, particularly fructose A systematic review and meta-analysis* What is the effect of different levels and forms of dietary fructose on the incidence or prevalence of NAFLD and on indices of liver health in humans? 16 *Funding was provided by the Technical Committee on Carbohydrates of the International Life Sciences Institute (ILSI) North American Branch. The sponsor had no role in study selection, quality assessment, synthesis or preparation of the manuscript. 17. Methods IOMs Standards for Systematic Reviews. Predefined study eligibility criteria: Populations: adults and children (4 years of age) with low (as defined in original studies) to no alcohol intake. Interventions/Exposures: free fructose, total fructose, sucrose, HFCS, and sugar-sweetened beverages (fructose of sucrose amount must be quantified). Outcomes: o Clinical outcomes: NAFLD or NASH diagnosis o Indices of liver health: intrahepatocellular lipids (IHCL), hepatic de novo lipogenesis (DNL), liver enzymes (ALT, AST, ALP, GGT), additional indicators of liver function, and liver fibrosis markers 17 18. Methods - continued All extracted data are available at SRDR (srdr.ahrq.gov/projects/64) Data synthases: Qualitative: rating the strength of the body of evidence based on risk of bias, consistency, directness and precision (AHRQ method guide)1 Quantitative: random-effects model meta-analysis2 when 2 studies with the same intervention and control for each outcome 18 1 Agency for Healthcare Research and Quality. Methods Reference Guide for Effectiveness and Comparative Effectiveness Reviews, Version 1.0. 2010 2 DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986 Sep;7(3):177-88. 19. Citations identified by searches in MEDLINE, CCRC, CAB Abstracts, Global Health databases from inception to April week 4, 2013 (n=2061) Articles retrieved for full-text review (n=99) Abstracts did not meet criteria (n=1943) 24 unique studies (in 25 artices) included Observational studies: n=5 3 case-control studies 2 cross-sectional studies Interventional studies: n=19** 11 pure fructose 6 sucrose 1 HFCS 1 honey 1 fructose reduction diet Articles did not meet criteria (n=76) Articles identified from published systematic reviews* (n=2) Chung, et al. in review (2014) Summary of Evidence Search and Selection *update search through March week 2, 2014 + 1 prospective cohort +3 interventional studies 2 pure fructose 1 fructose reduction diet in NAFLD patients 20. Observational studies (n=6) 20 Outcome of interest Population Studies, n (Total Sample Size) Risk of Bias (References) Consistency Directness Precision Main Findings NAFLD (various diagnostic criteria) Adults 3 case-control studies (81 cases; 40 hospital controls) 3 high risk Consistent Direct Imprecise Unadjusted analyses showed significantly higher mean (SE) daily fructose intake in NAFLD cases (n=32) than controls (n=16) NAFLD cases: 52 (5.2) to 58 (4.4) g/d [=208 to 232 kcal/d from dietary fructose] Controls: 40 (3.8) to 41 (3.2) g/d [=160 to 164 kcal/d from dietary fructose] NAFLD cases (n=49) reported significantly higher mean (SE) daily consumption of HFCS or sugar containing beverages than controls (matched by age, gender, and BMI) (n=24) NAFLD cases: 365 (NR) kcal/d Controls: 170 (NR) kcal/d Hepatic fat fraction (MRI) Hispanic overweight children from community 1 cross-sectional study (n=153) 1 medium risk NA Hepatic fat fraction (%) was not significantly associated with total dietary sucrose intake (%kcal/d, or g/d with energy as a covariate) Liver enzymes Children with fatty liver; older adults 1 cross-sectional study in children (n=38); 1 prospective cohort study in older adults (n=886) 1 high risk; 1 low risk Inconsistent Indirect Precise In the best fit multivariate models (r 2 =0.96, P=0.001), higher intakes of fructose were associated significantly with higher GGT levels (P=0.03) Sugar intake (% total carbohydrate intake) was not associated with ALT or GGT in multivariable concurrent change analyses from baseline to 5- 21. Observational studies The overall strength of evidence was rated insufficient due to the high risk for biases and inconsistent study findings. 4 studies (all rated at high ROB) consistently reported higher dietary fructose and/or sucrose intakes were associated with higher risks of developing or progression of NAFLD Sugar intake was not associated with indices of liver health (HHF, ALT and GGT) in 1 cross-sectional study (medium ROB) in children and 1 prospective cohort study (low ROB) in adults. 21 Chung, et al. in review (2014) 22. Chung, et al. in review (2014) Evidence Map of Intervention Studies That Examined the Effects of Fructose or Sucrose on Indices of Liver Health 23. 23 Intra-hepatocellular lipids (IHCL) outcome Hypercaloric fructose vs. WM diet Chung, et al. in review (2014) 24. 24 Intra-hepatocellular lipids (IHCL) outcome Hypercaloric fructose vs. glucose Chung, et al. in review (2014) 25. 25 Liver enzyme outcomes Chung, et al. in review (2014) 26. Intervention studies Low level of evidence: Hypercaloric fructose diet can increase liver fat and AST concentrations in healthy men compared with a weight maintenance diet. However, there is a high potential for selected outcome reporting bias that can lead to false positive meta-analysis finding. Hypercaloric fructose and glucose diets have similar effects on liver fat and liver enzymes in healthy adults. Insufficient evidence to draw a conclusion for the effects on hepatic DNL based on results from single RCT (Stanhope et al. J Clin Invest. 2009;119(5):1322-34 ). 26 Chung, et al. in review (2014) 27. Limitations Most studies; Rated at medium or high risk of bias Small sample size Included healthy adult men only Were highly heterogeneous in study design and intervention, limiting comparability. 28. Conclusions Based on indirect comparisons across study findings, the apparent association between indices of liver health (i.e., liver fat, hepatic DNL, ALT, AST, and GGT) and fructose or sucrose intake appear to be confounded by excessive energy intake. The available evidence is not sufficiently robust to draw conclusions regarding the effects of fructose, HFCS, or sucrose consumption on NAFLD. 29. Systematic Review Research Team Mei Chung, PhD, MPH Jiantao Ma, MD, MS Kamal Patel, MPH, MBA Samantha Berger, BS Joseph Lau, MD Alice H. Lichtenstein, DSc 30. Email Webinar Survey Monkey In-person Meeting Building Evidence Map Step 1 Building Evidence Map Step 2 Identifying Evidence Gaps Prioritizing Research Topics Refine Eligibility Criteria Refine Research Questions Rank Outcome Importance Participate in Manuscript Writing Literature Search Stakeholders Role FRN Assessment: Sugars and Health 30 31. Diverse and balanced stakeholder panel 31 FRN Sugars and Health Stakeholder Panel Health Provider Lay Audience Research Funder Policy Maker Evidence-based Methodologist Researcher (Intervention) Researcher (Epidemiology) Researcher (Statistics) Product Maker (non-voting) 32. Top 15 FRN: Sugars and Liver Fat What are some factors that may modify effects of sugar intake on liver fat Does sugars consumption contribute to fatty liver independent to all other factors? Does sugar intake modify liver fat in the absence of a hypercaloric diet? Considerations: Age, race and ethnicity. Alcohol-sugar interaction. Exercise is major determinant of liver fat. Role of sugar in progression of NASH and NAFLD. Hepatic glucose output; Transition from fatty liver to liver dysfunction Obesity/type 1 and 2 diabetes/metabolic disease 32 33. Crosscutting FRN issues Future research should use experimental conditions approximating current intake levels and chemical forms (pure fructose does not exist in a typical diet), so that the results can inform dietary intake recommendations for disease prevention. 33 34. Future Research Needs Research Team Tufts University Research Team Mei Chung, PhD, MPH; Ding Ding (Deena) Wang, MPH; Samantha Berger, BS; Dzidzor Sackey, BS Stakeholders Ed Archer, PhD USC Janine Higgins, PhD University of Colorado Sery Kim, Esq. Washington, DC Maren Laughlin, PhD NIDDK Lu Qi, MD, PhD Harvard University Susan Raatz, PhD USDA Joanne Slavin, PhD, RD, UMN University of Minnesota Joanne Spahn, PhD USDA, CNPP Dan Steffen, PhD (nonvoting) Ret. Krafts Foods, FL Richard Siegel, MD Tufts Medical Center Hope Warshaw, MS, RD, CDE Washington, DC + One evidence-based methodologist from a government agency 35. How Sweet is the Evidence in Policy? Roger Clemens, DrPH, CFS, CNS, FIFT, FACN, FIAFST Chief Scientific Officer, Horn rclemens@ethorn.com Research Professor, USC School of Pharmacy clemens@usc.edu USC Health Center Pharmacy 36. 36 The Evolution of Food Control DegreeofSpecificity Degree of Command & ControlCourtesy of Bill Layden Information Regulation No Good Food/Bad Food; All Foods Fit Better-for-you Foods Restrictions on license to sell; zoning restrictions Litigation, class action suits Government audits on sales based on usage, nationalized food companies Self-regulation based on nutrition standards Nutrition standards used to tax, restrict marketing & advertising, restrict access, limit eligibility in food assistance Warning labels, changes to GRAS status Ban, ration 37. Sugar in the News Posted: August 24, 2009; Accessed: February 2, 2014 37 38. Policy Statements by Medical Associations 38 American Medical Association Taxes on beverages with added sweeteners are one approach to addressing the obesity epidemic. AMA, 2012 American Academy of Pediatrics Atax on [SSBs] woulddissuade parents, children and other consumers from purchasing these unhealthy products AAP, 2014 American Heart Association / American Stroke Association Advocates fordetermining the impact of beverage sales taxes or excise tax[partly] dedicated for preventionat the time of sale[of] at least a penny per ounceno sunset. AHA/ASA, 2013 American Cancer Society [In NY State] enacted a 1 cent per ounce SSB tax to counter the impact of food deserts and reduce consumption of sugary drinks. Whalen, 2011 American Diabetes Association There is now abundant evidence fromindividuals without diabetes thatlarge quantities of SSBs should be avoided to reduce the risk for weight gain and worsening of cardiometabolic risk factors. Diabetes Care, 2014 39. Policy Statements by Public Health Organizations 39 Association of State and Territorial Health Officials Food marketing that restrict[s] the marketing of SSBs to children under the age of 18, near schools or other places where youth gather. ASTHO, 2012 Brookings Institution such a tax would end up being highly regressivemay provide a disincentive to purchase SSBs, it would not necessarily encourage these groups to purchase healthier foods as a substitution. Brookings, 2013 Center for Science in the Public Interest A 1/oz excise tax on SSBs could raise $296 MM/yr [in the state of MD] Disease-promoting beverages like Coca-Cola and Pepsi should never have become the default restaurant beverage CSPI, 2010 & 2014 American Public Health Association supportenacting excise taxes which would raise the average price of all [SSBs] a significant contributor to the obesity epidemic, and increases the risk for T2D, heart disease and dental decay. APHA, 2012 Institute of Medicine substantial and specific excise taxes on SSBswith the revenues being dedicated to obesity prevention programs educate the public about the risks associated with overconsumption of [SSBs] IOM, 2012 National Association of County & City Health Officials Local health departments should workto ensure that warning messages about the dangers of SSB consumption are distributed NACCHO, 2013 40. Sugar in Research 14 15 16 17 18 NHANES 1988-1994 NHANES 1999-2004 NHANES 2005-2010 EstimatedMean(95%CI) Percent Calories from Added Sugar Yang et al., JAMA Intern Med 2014; doi:10.1001/jamainternmed.2013.13563 40 41. WHO The issue: free sugars contribute to untoward health effects Dental caries Maintain or reduce body weight Free sugars monosaccharides and disaccharides added to foods by the manufacturer, cook or consumer, and sugars naturally present in honey, syrups, fruit juices and fruit concentrates. 41WHO, Draft guidelines on free sugars released for public consultation, 5 March 2014 42. WHO Recommendations Reduce intake of free sugars throughout the life- course (strong recommendation1). Intake of free sugars not exceed 10% of total energy2 (strong recommendation). Intake of free sugars reduce to below 5% of total energy (conditional recommendation3). 42WHO, Draft guidelines on free sugars released for public consultation, 5 March 2014 43. Practicality 43 Food 2 servings Energy (kcal) Free Sugar (g) Total % EER Blueberries (fresh frozen, smoothie) 168 29.48 5.9 Bananas (fresh, in smoothie) 268 36.68 7.3 Tangerines (snacks on ride) 206 41.26 8.3 Potatoes (raw, snacks) 104 1.94 0.4 Green beans (fresh) 62 6.52 1.3 Almonds (raw) 328 2.38 0.5 Walnuts (raw) 370 6.26 1.3 44. Sugar in Research Yangetal.,JAMAInternMed2014;doi:10.1001/jamainternmed.2013.13563 Conclusions: Increased calories from added sugar associated with increased risk of CVD mortality Consumption of SSB (aka sugar) is associated with elevated CVD mortality Recommendation Limit intake of calories from added sugar Headlines: Drink just one 12-ounce can of sugary soda every day, and you might be unwittingly increasing your risk of dying from heart disease, suggests a new study. 44 45. Proposed Nutrition Facts Panel Assist consumers to comply with 2010 DGAC No analytical methods for added sugars Food producers must provide information and maintain records for 2 yrs verify the declared amount of added sugars in specific foods, alone or in combination with naturally occurring sugars, where the added sugars are subject to fermentation. 45 Federal Register / Vol. 79, No. 41 / Monday, March 3, 2014 / Proposed Rules 46. Is there a demon in the field? 0 100 200 300 400 500 600 0 5 10 15 20 25 30 35 40 1960- 1962 1971- 1974 1976- 1980 1988- 1994 1999- 2000 2007- 2008 2009- 2010 Kcal/d Prevalence(%) Caloric Sweeteners HFCS Overweight Obese 46 U.S. Dept of Agriculture. Economic Research Service 47. 2010 Dietary Guidelines In adults, what are the associations between intake of sugar-sweetened beverages and energy intake and body weight? Limited evidence shows that intake of SSB in linked to higher energy intake in adults. Moderate body of epidemiologic evidence suggest that greater consumption of SSB is associated with increased body weight in adults. Moderate body of evidence suggests that under isocaloric controlled conditions, added sugars, including SSB, are no more likely to cause weight gain than any other source of energy. 47 48. The Evidence 48 isoenergetic exchange of sugars with other carbohydrates was not associated with weight change. Te Morenga et al., BMJ 2012;345:e7492 doi: 10.1136/bmj.e7492 observational studies suggest a possible relationship between consumption of SSB and body weight, [however] there is currently insufficient supporting evident from RCTs of sufficient size and duration van Baak and Astrup, Obesity Rev 2009;10(suppl 1):9-23 49. Whats Driving Policy? 49 strongest evidence for public health and health outcomes is from RCTs; [there] should be caution when communicating recommendations when clinical evidence or dietary intervention data are not available. Maki et al., Adv Nutr 2014;5(1):7-15 epidemiological studies [and statistical modeling from NHANES III] suggest higher intake of added sugar (>10%en) is associated with increased risk for CVD mortality. Yang et al., JAMA Intern Med 2014; doi: 10.1001/jamainternmed.2013.13563 50. International Guidelines and Policies 50 Approximately 60 countries recommend limit intake of added sugar Recommendations vary: qualitative, quantitative (energy based) Primary focus varies: dental caries, CVD, obesity promote healthful lifestyles Culturally appropriate foods Sanitation Clean water 51. European Countries 51 Europe (about 50 countries, 28 in EU) Diverse recommendations and advisories Some recommend limit sugar 10-15%en Some recommend general limit of sugar intake Some recommend limit SSB consumption 52. Taxation on SSB in USA 52 Jou & Techakehakij. Health Policy 2012;107:83-90 Andreyeva et al., Prev Med 2011;52:413-6 Barry et al., Am J Prev Med 2013;44:158-63 Kotakorpi K. Econ Lett 2008;98:95-9 41% 60% 58% 54% 53% 51% 49% SSBs are the single largest contributor to obesity A tax on SSBs . . . Agree Agree Agree Agree Agree Agree Agree Is arbitrary because it does not affect consumption of other unhealthy foods Is viewed as a quick way for politicians to fill budget holes Is viewed as an unacceptable intrusion of government into peoples lives Is viewed as being opposed by most Americans Is viewed as being harmful to the poor Would raise revenue for obesity prevention efforts 53. Public SSB Consumption Strategy in USA 53 Gollust et al., Prev Med 2014;63:52-57 SSBs are the single largest contributor to obesity Is arbitrary because it does not affect consumption of other unhealthy foods Is viewed as a quick was for politicians to fill budget holes Is viewed as an unacceptable intrusion of government into peoples lives Is viewed as being opposed by most Americans Is viewed as being harmful to the poor would raise revenue for obesity prevention efforts 0% 5% 10% 15% 20% 25% 30% Strongly Oppose Oppose Somewhat Oppose Neither Somewhat Support Support Strongly Support DistributionofSupport Taxation Prohibit (>16 oz) Prohibit Advertising Require PSA Prohibit Sales by Schools Require Prominent Labels Internet survey (n=1319), ages 18-64; Fall 2012 Key Findings: Greatest support for calorie labeling (65%) and removal from schools (62%) Lowest support for taxes (22%) or portion size restrictions (26%) 54. Taxation on SSB California Taxation rejected by majority of voters (Nov 2012) No direct evidence that SSB taxation decreased BMI or obesity Taxation on ballot in several cities (Nov 2014) SSB banned in some city-sponsored events 54 Taber et al., Arch Pediatr Adolesc Med 2012;166:256-62 55. Consumer (aka Consumption) Taxation 55 Europe (value-added tax) and Australia (general service tax) Intended to encourage more healthful food consumption patterns No evidence of improved health outcomes Majority of EU members eliminated SSB taxation Waterlander et al., Prev Med 2012;54:323-30 Caraher & Cowburn. Pub Health Nutr 2005;8:1242-9 Powell & Chaloupka. Milbank Q 2009;87:229-57 Edwards RD. Prev Med 2011;52:417-8 56. Virtual Supermarket RCT 0.0 1.0 2.0 3.0 4.0 5.0 6.0 SSB (litre) Light (diet), Bottled Water (litre) Dairy Drinks (litre) Coffee/tea (# of items) Alcoholic Drinks BeveragePurchases (meanSD) Control Taxation 56 Waterlander et al., Appetite 2014;78C:32-9 P=0.09 P=0.67P=0.63P=0.26 P=0.08 Background: Dutch increased VAT from 6% to 19% Study: 102 participants randomized to one of two study groups. ~28% reduction 57. Ban SSB in Schools Adopted by 34 states Reduce availability of SSB on school campuses as part of National School Lunch Program Increase access to bottled water Student reactions Seek alternative environments to purchase SSB- type products No impact on purchasing, consumption, BMI 57 Taber et al., Arch Pediatr Adolesc Med 2012;166:256-62 Moran et al., Report to Robert Wood Johnson Foundation, 2006 Mello et al., Am J Pub Health 2008;98:595-604 Johnson et al., J Adolesc Health 2009;45(suppl):S30-37 Woodward-Lopez et al., Am J Public Health 2010;100:2137-45 Cullen et al., Am J Public Health 2008;98:111-17 Cunningham & Zavodny. Soc Sci Med 2011;73:1332-39 58. Key Messages The prevalence of obesity is a global public health burden No clinical study on SSB and obesity/BMI The global efforts to reduce the prevalence obesity and overweight include approaches in dietary guidelines, taxation on sugar-sweetened beverages (SSB), and restricted access to these products Statutory efforts directed to SSB have produced inconsistent results relative to changes in BMI and obesity in targeted populations 58 59. Do fructose-containing sugars lead to adverse health consequences? Results of recent systematic reviews and meta-analyses John L Sievenpiper, MD, PhD1,2,3 1Scientist, Li Ka Shing Knowledge Institute, Toronto, ON, CANADA 2Knowledge Synthesis Lead Toronto 3D Knowledge Synthesis and Clinical Trials Unit Clinical Nutrition and Risk Factor Modification Centre, St. Michaels Hospital, Toronto, ON, CANADA 3Resident Physician, Department of Pathology and Molecular Medicine, Faculty of Health Sciences, McMaster University, Hamilton, ON, CANADA. Sugars and Health Controversies: What does the science say? Experimental Biology San Diego, CA April 26, 2014 60. Disclosures (over past 24 mos) Board Member/Advisory Panel Canadian Diabetes Association (CDA) 2013 Clinical Practice Guidelines Expert Committee for Nutrition therapy European Association for the Study of Diabetes (EASD) 2015 Clinical Practice Guidelines Expert Committee for Nutrition therapy American Society for Nutrition (ASN) writing panel for a scientific statement on the metabolic and nutritional effects of fructose, sucrose and high fructose corn syrup International Life Science Institute (ILSI) North America, Food, Nutrition, and Safety Program (FNSP) Advisory Board Transcultural Diabetes Algorithm (tDNA) Group Diabetes Nutrition Study Group (DNSG) of the European Association for the Study of Diabetes (EASD) executive committee Research Support Canadian Institutes of Health Research (CIHR) Calorie Control Council The Coca Cola Company (**unrestricted, investigator initiated education grant**) Pulse Canada International Tree Nut Council Nutrition Research & Education Foundation Dr. Pepper Snapple Group(**unrestricted, investigator initiated donation**) Honouria and Speaker fees National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of health (NIH) American College of Physicians (ACP) American Society for Nutrition (ASN) American Heart Association (AHA) Canadian Nutrition Society (CNS) Canadian Diabetes Association (CDA) International Life Sciences Institute (ILSI) North American International Life Sciences Institute (ILSI) Brazil Pulse Canada Abbott Laboratories Calorie Control Council The Coca Cola Company Canadian Sugar Institute Dr. Pepper Snapple Group Other Spouse is an employee of Unilever Canada Editorial Board, American Journal of Clinical Nutrition Associate Editor, Frontiers in Nutrition, Nutrition Methodology Special Issue ("Sugar and Obesity) Editor, Nutrients 61. 1972 John Yudkin 1964 Ancel Keys 19701952 The great debate: Fat versus sugar 62. Vuilleumier S.. Am J Clin Nutr 1993;58(suppl):733S6S. Flegal KM, et al. JAMA 2002;288:17237. Bray GA, et a. Am J Clin Nutr. 2004 Apr;79(4):537-43 Ecological relationship between fructose intake and prevalence of Overweight/Obesity:1961-2000 George Bray 2004 Overweight Obesity Total fructose Free fructose HCFS 63. Harper's Illustrated Biochemistry, 27th ed, 2006 Fructose as an unregulated substrate for de novo lipogenesis (DNL) Phosphofructokinase Dietary Fructose Dietary Glucose Glycerol-3P Fatty acid synthesis TAGs 64. Metabolic fate of fructose in humans: A review of oral and liver catheterization, stable isotope studies Sun SZ, Empie MW. Nutr Metab 2012;9:89 DNL 1000), dose = 22.5-300g/d, FU = 1-52wk Benefit Harm Cardiometabolic endpoint Comparisons N Standardized Mean Difference (SMD) with 95% CI I2 Body weight (22) 31 637 -0.22 (-0.58, 0.13) 37%* Fasting Lipids (16,159) TG TC LDL-C HDL-C 48 31 20 27 809 569 313 425 0.24 (-0.05, 0.52) 0.30 (-0.05, 0.65) -0.09 (-0.53, 0.35) 0.38 (0.00, 0.75) 77%* 96%* 100%* 100%* Postprandial TG (160) 14 290 0.14 (-0.02, 0.30) 54%* Glycemic control (20,158) GBP FBG FBI 19 43 32 276 823 563 -0.28 (-0.45, -0.11) -0.10 (-0.40, 0.20) -0.32 (-0.66, 0.03) 50%* 78%* 87%* Blood pressure (21) SBP DBP MAP 13 13 13 352 352 352 -0.39 (-0.93, 0.16) -0.68 (-1.23, -0.14) -0.64 (-1.19, -0.10) 31% 47%* 97%* Uric acid (157) 18 390 0.04 (-0.43, 0.50) 0% NAFLD (161) IHCL ALT 4 6 95 164 -0.09 (-0.36, 0.18) 0.07 (-0.73, 0.87) 0% 0% -4 -3 -2 -1 0 1 2 3 4 114. Addition trials 115. Harm in hypercaloric trials: An effect more attributable to energy (up to +250g/d +50% E) Benefit Harm Cardiometabolic endpoint Comparisons N Standardized Mean Difference (SMD) with 95% CI I2 Body weight (22) 10 119 1.24 (0.61, 1.85) 30% Fasting lipids (16,159) TG TC LDL-C HDL-C 7 5 4 4 122 102 95 79 1.05 (0.31, 1.79) 0.39 (-0.50, 1.25) 0.22 (-0.77, 1.19) 0.00 (0.00, 0.00) 87%* 89%* 96%* 100%* Postprandial TG (160) 2 32 0.65 (0.30, 1.01) 22% Glycemic control (20,158) GBP FBG FBI 2 8 8 31 98 98 -0.33 (-0.62, -0.04) 1.32 (0.63, 2.02) 0.95 (0.26, 1.64) 0% 59%* 41% Blood pressure (21) MAP 2 24 -0.76 (-2.15, 0.62) 24% Uric acid (157) 3 35 2.26 (1.13, 3.39) 0% NAFLD (161) IHCL ALT 5 4 60 59 0.45(0.18, 0.72) 0.99 (0.01, 1.97) 51%* 28% -4 -3 -2 -1 0 1 2 3 4 116. CONCLUSIONS 117. Conclusions: Trials 1. There is a moderate body of consistent evidence from controlled feeding trials that fructose at low to moderate doses does not harm body weight, serum fasting or postprandial lipids, uric acid, and NAFLD and may even benefit blood pressure and glycemic control in humans. 2. There is an emerging body of consistent evidence from controlled feeding trials that fructose consumed under hypercaloric feeding conditions may promote weight gain, fasting and postprandial dyslipidemia, raised uric acid levels, and NAFLD, effects which appear more attributable to the excess energy than the fructose itself. 3. The shorter duration, poor quality and heterogeneity in the available trials creates some uncertainty about the true effects of fructose. There is a need for larger, longer-term, higher quality real world feeding trials to guide our understanding of the metabolic effects of fructose. 118. Take away message 119. Take away message 1. Like with the earlier fat story, it is difficult to separate the contribution of fructose-containing sugars from that of other factors in the epidemic of obesity and cardiometabolic disease, owing to the small effect sizes and lack of demonstrated harm over other sources of excess energy in the diet 2. There are many pathways to overconsumption leading to weight gain and its downstream consequences. Dietary patterns have the greatest influence on weight gain and cardiometabolic risk and represent the best opportunity for successful interventions. 3. Attention needs to remain focused on reducing overconsumption of all caloric foods (including sugary beverages and foods!) and promoting greater physical activity. 120. Acknowledgements Arash Mirrahimi, HBSc, MSc (Coordinator, Co-I) Amanda J Carleton, MSc (MD student, Co-P) Dr. Sonia Blanco MD, MSc (Coordinator) Laura Chiavaroli, MSc (PhD Candidate) Adrian I Cozma, HBSc (Research Assistant) Vanessa Ha, HBSc (MSc Candidate) David Wang, HBSc (Project Student) Simon Chiu (Project Student) Matt E Yu, HBSc (Project Student) Viranda (Jay) Jayalath (Project Student) Christine Tsilias (Project Student) Reem Tawfik (Project Student) Sara Rehman (Project Student) Vivian Choo (Project Student) Dr. Alexandra L Jenkins, PhD, RD (Decision Maker) Prof. Lawrence A Leiter, MD (Decision Maker) Prof. Thomas MS Wolever, MD, PhD (Decision Maker) Dr. Russell J de Souza, ScD, RD (PDF, Co-I) Dr. Marco DiBuono, PhD (Decision Maker) Prof. Joseph Beyene, PhD (Co-I) Prof. David JA Jenkins MD, PhD, DSc (PI) Prof. Cyril WC Kendall, PhD (Co-I)