The Current and Emerging Knowledge and Research on Non-Nutritive Sweeteners November 16, 2018 (1-2 PM EST)
Agenda 1:00 PM Welcome and Introduction Andrew Zajac, U.S. Food and Drug Administration 1:05 PM Low-Calorie Sweeteners: Consumption Trends and Findings of Mechanistic and Observational Studies Allison Sylvetsky, Milken Institute School of Public Health, The George Washington University 1:25 PM The Effects of Low-Calorie Sweeteners on Weight Loss and Metabolic Outcomes: Evidence from Randomized Controlled Trials Frank Hu, Harvard T.H. Chan School of Public Health 1:45 PM Q&A 2:00 PM Adjourn
Low-Calorie Sweeteners: Consumption Trends and Findings of Mechanistic and Observational Studies Allison Sylvetsky Milken Institute School of Public Health, The George Washington University
No conflicts of interest
Low-calorie Sweeteners Also known as artificial sweeteners, non-nutritive sweeteners, high-potency sweeteners, sugar substitutes Potently sweet and contain no or few calories In this presentation, we will not be discussing sugar alcohols.
Safety of LCS Numerous toxicology and clinical studies demonstrate that LCS are generally safe and welltolerated Conducted across species, across FDA-approved sweeteners, at many dosages Focus of this presentation is not safety but rather LCS effects on weight and metabolic health
LCS consumption in the United States Sylvetsky et al. AJCN 2012; Sylvetsky et al. JAND 2017
LCS consumption in the United States Beverages are the most commonly consumed source of LCS Prevalence of LCS use increases with age, family income, educational attainment, and body weight and is most common among females and non-hispanic white individuals Significant increases in LCS consumption observed over past two decades across all sociodemographic subgroups Sylvetsky et al. AJCN 2012; Sylvetsky et al. JAND 2017
LCS in Foods and Beverages
Sylvetsky, & Dietz NEJM 2014; Sylvetsky et al., Int. J Peds, 2014, Sylvetsky et al. AJCN 2017
LCS use and weight gain: cohort studies Azad CMAJ 2017
Miller & Perez AJCN, 2013
LCS and diabetes risk: cohort studies Azad CMAJ 2017
Inter-generational effects? Azad et al. 2016, JAMA Peds
How to explain epidemiologic findings? Pepino 2015 Phys & Behavior
Proposed mechanisms Pepino, Diabetes Care 2015, Brown & Rother, JCEM 2012
Most of these mechanisms have not been studied after chronic LCS exposure in humans!????????
Taste receptor signaling Taste receptors are not only in the oral cavity! There are sweet taste receptors in the pancreas, gut, lungs, adipose, etc.
Higher insulin levels?
Increased adipogenesis?
Saccharin exposure -> weight gain in rats Rats given unrestricted access to standard laboratory chow and plain unsweetened yogurt 3x per week and sweetened yogurt (glucose or saccharin) 3 times per week for 14 days. Swithers et al. Behav Brain Res, 2012
Is this applicable to humans? Does intermittent exposure reflect consumption in humans? Is this effect specific to LCS administered in yogurt? Rodent chow vs. human diet?
LCS and gut microbiome 10 week old mice fed high fat diet supplemented with saccharin for 11 weeks Suez et al., Nature 2014
Suez et al., Nature 2014 LCS and gut microbiome 6 days following transfer of fecal samples from donor mice drinking saccharin, glucose, water to germfree mice
Do LCS influence gut microbiome in humans?
Summary LCS consumption has increased over the past two decades Foods and beverages with LCS are widespread in the food supply LCS exert metabolic effects in vitro and in rodents Relevance to chronic exposure in humans is unclear
The Effects of Low-Calorie Sweeteners on Weight Loss and Metabolic Outcomes: Evidence from Randomized Controlled Trials Frank Hu, Harvard T.H. Chan School of Public Health
Disclosures Supported by the National Institute of Health grants R01 DK102896, R01 HL060712, and R01 HL118264. Received grants from the California Walnut Commission and lecture honorarium from Standard Process and Metagenics. Outside the presented work.
Findings from observational studies showed no association between low-calorie sweeteners (LCS) intake and body weight or fat mass and a small positive association with BMI. Data from RCTs indicate that substituting LCS options for their regular-calorie versions results in a modest weight loss and may be a useful dietary tool to improve compliance with weight loss or weight maintenance plans. Am J Clin Nutr 2014;100:765 77.
Meta-analysis of RCTs (4 week to 40 month interventions) showed that consumption of LCS vs sugar led to reduced BW (nine comparisons; 1.35 kg, 95% CI 2.28 to 0.42), and a similar reduction in BW versus water (three comparisons; 1.24 kg, 95% CI 2.22 to 0.26). Evidence from RCTs indicates that LCS do not increase EI or BW, whether compared with caloric or non-caloric control conditions. Overall, evidence indicates that use of LCS in place of sugar, in children and adults, leads to reduced EI and BW, and possibly also when compared with water.
Interpretation: Evidence from RCTs does not clearly support the intended benefits of LCS for weight management, and observational data suggest that routine intake of LCS may be associated with increased BMI and cardiometabolic risk. Further research is needed to fully characterize the long-term risks and benefits of LCS.
RCTs: Substituting nutritive sweeteners with LCS Meta-analysis of 13 RCTs Displacing sugar sweetened beverages (SSBs) or sugar with LCS options may result in modest weight loss Miller & Perez. Am J Clin Nutr 2014.
RCTs: Substituting nutritive sweeteners with LCS Miller & Perez. Am J Clin Nutr 2014.
RCTs: LCS and Body Weight Rogers et al. Int J Obesity 2016. Meta-analysis of 9 sustained intervention RCTs Consumption of LCS vs SSB led to reduced body weight
LCS and body weight: RCTs with non-caloric comparators Interpretation: LCS not associated with weight loss in meta-analysis of 5 RCTs, except in long-term ( 12 mo) trials with industry sponsorship. Evidence from RCTs does not clearly support use of LCS for weight management. Azad et al. CMAJ 2017.
Aspartame and Weight Loss Trial n = 163 obese women These data suggest that participation in a multidisciplinary weight control program that includes aspartame may facilitate the long-term maintenance of reduced body weight. Blackburn et al., Am J Clin Nutr 1997.
n = 303 overweight/obese individuals Water Diet Beverage In a weight loss program, LCS beverage consumers who were asked to consume LCS beverages (24 oz/day) lost significantly more weight and maintained significantly greater weight losses over 1 year than participants asked to stop LCS beverage consumption and consume water alone (24 oz/day). These results support the use of LCS beverages to help with weight loss and maintenance. Obesity 2016
Effects of sucrose-sweetened beverages vs. other beverages on fat distribution: a 6-month RCT Overweight subjects (n= 47) randomly assigned to 4 different test drinks (1 L/d ) Daily SSB intake for 6 months increased ectopic fat accumulation and lipids compared with diet cola, milk and water Maersk et al. Am J Clin Nutr 2012.
Replacing Caloric Beverages with Water or Diet Drinks N = 318 adults; 280+ kcal/d of caloric beverages Water and Diet Beverage interventions decreased energy intake from beverages. DB group increased likelihood of significant weight loss; better adherence for DB. Water group had significant reduction in fasting glucose and improved hydration status vs controls Replacing SSB with either DBs or water, based on the consumers preference and ability to adhere, appears warranted at this stage of research. AC = Attention control; WA= Water Intervention; DB = Diet Beverage Intervention Tate DF et al., Am J Clin Nutr, 2012.
Replacing Caloric Beverages with Diet Drinks N = 641 normal weight, 4-12 yr old children Trial duration: 18 mo; 104 kcal/d of sugar-sweetened beverage (n=322) or diet beverage (n=319) Urinary sucralose concentrations as biomarker de Ruyter et al. N Engl J Med 2012.
Replacing Caloric Beverages with Water or Diet Drinks N = 224 overweight & obese adolescents 1-yr intervention + 1-yr follow-up; multi-component intervention (home delivery of bottled water/diet drinks) Ebbeling et al. N Engl J Med 2012.
Aspartame Consumption and Glycemia, Appetite, Body Weight 100 healthy lean adults randomly assigned to daily beverage containing 0, 350, or 1050 mg aspartame for 12 weeks (95% compliance) 350 mg 1 can low-calorie soda No effect on body weight, appetite, body composition, glucose, insulin, resting leptin, glucagon-like peptide 1 or gastric inhibitory peptide Findings do not indicate that using aspartame as a substitute for energy-yielding sweeteners would be problematic Higgins et al. J Nut. Apr 2018.
Conclusions: Findings suggest that daily consumption of 2 cans of a beverage containing aspartame and acesulfame K over 12 wk has no significant effect on insulin sensitivity and secretion in nondiabetic adults. J Nutr 2018;148:1293-1299
Sucralose decreases insulin sensitivity in healthy subjects: a randomized controlled trial Healthy subjects with low habitual consumption of LCS (n = 33/group) Moderate consumption of sucralose (15% of Acceptable Daily Intake) over 14 d associated with significantly decreased insulin sensitivity Median change -17.7% compared to -2.8% in the control group Conclusion: Nutritional treatment of obesity and diabetes should focus on improving diet and increasing physical activity without promoting sweettasting foods regardless of whether they contain caloric sweeteners or LCS Romo-Romo et al. Am J Clin Nutr 2018.
Limitations of Observational Studies of LCS and Body weight Reverse causation Residual confounding by other dietary behaviors or lifestyle factors Measurement error in dietary intake assessment Rare outcomes require very large sample sizes and long follow-up duration Evidence on intergenerational effects is limited
Changes in beverage intake and long-term weight gain Adjusted for: age, baseline BMI and changes in diet, smoking, exercise, alcohol, sleep duration, TV watching Pan et al., Int J Obes (Lond). 2013 October ; 37(10): 1378 1385
Limitations of RCTs on LCS and Weight Control Small sample size, short follow-up Decreased compliance and high dropout rates Choice of comparison group Poorly defined interventions Do not reflect real-world consumption patterns Different types of LCS Adults vs. children Healthy individuals vs. clinical patients
Current Recommendations 2015-2020 Dietary Guidelines for Americans (DGA) Replacing added sugars with LCS may reduce calorie intake and improve weight control in the short-term but little is known about long-term effects.
American Heart Association/American Diabetes Association Scientific Statement Insufficient data to determine whether using LCS to replace caloric sweeteners reduces added sugar or carbohydrate intakes benefits appetite, energy balance, body weight, or cardiometabolic risk factors. Some evidence that LCS could facilitate reductions in added sugar intake, decreasing total energy and aiding with weight loss/control. However, potential benefits will not be fully realized if there is a compensatory increase in energy intake from other sources. Gardner et al. Circulation 2012.
AHA Science Advisory: Low-Calorie Sweetened Beverages and Cardiometabolic Health Beverages are most common source of LCS intake Children should not drink LCS beverages long-term because effects are unknown For adults who are regular SSB consumers, LCS beverages may be a temporary strategy to reduce SSB intake Alternatives to LCS beverages and SSBs (ex. plain, carbonated, or unsweetened flavored waters) should be encouraged Further research needed on the effects of LCS beverages on weight control, cardiometabolic risk factors, risk of cardiovascular disease and other chronic diseases Johnson et al. Circulation 2018.
Summary and Conclusions RCTs and observational studies of LCS and weight and metabolic outcomes have mixed and somewhat conflicting findings Some short-term evidence suggests that replacing SSBs with LCS beverages could help in management of overweight/obesity, but longerterm and higher quality trials are needed Need more evidence on long-term effects of LCS consumption on cardiometabolic diseases, cancer, mortality, and other health outcomes Improving assessment of LCS intake: Update food databases to accurately reflect LCS content in food/beverages and biomarkers to assess intake and compliance
Summary and Conclusions LCS can be consumed at moderate levels to replace SSBs to reduce energy intake and control weight, but water/healthy alternatives are preferable Regular intake during childhood not recommended Longer-term RCTs needed to explore LCS: By type (due to unique sensory and metabolic profiles) By food/beverage source At different intake levels and across different populations
Q&A
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