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What we know—and don’t—about non-nutritive sweeteners
An estimated 93.3 million Americans (roughly 40% of the US population) were obese in 2015-2016, and most of them had at least 1 chronic disease.1 As a result, patient education focused on lifestyle modification, including healthy nutrition and physical activity, has become an integral part of our everyday practice.
At the same time, the most recent dietary guidelines recommend that added sugar make up < 10% of daily calories.2 In the United States, low-calorie food and beverages containing non-nutritive sweeteners (NNSs; TABLE3-8) have become a popular means of keeping the sweetness in our diet without the health ramifications associated with sugar. These NNSs (aka, artificial sweeteners, high-intensity sweeteners, and non-caloric sweeteners) are ubiquitous in soft drinks, processed grains (including breads, cereals, and granola bars), and dairy products (including yogurts, flavored milk, and ice cream). As examples, NNSs are present in 42% of flavored waters, 33% of yogurts, and all diet beverages.9,10 They can even be found in medications, multivitamins, toothpaste, and mouthwash.
Business is booming
Global NNS consumption has been growing more than 5% per year, meaning that by 2020, NNSs are expected to be a $2.2 billion industry.11 One study using data from the National Health and Nutrition Examination Survey (NHANES) found that the use of NNSs in the United States increased from 21.1% in 2003 to 24.9% in 2009-2010 among adults and increased from 7.8% to 18.9% over the same time period among children.12
The main increase in the consumption of NNSs across all age groups has been via the consumption of beverages. Approximately 11% of healthy weight, 19% of overweight, and 22% of obese adults consume diet beverages.13,14 Consumption of diet beverages or NNSs increases with age12 and is especially common among women with higher levels of education and income.15
However, concerns remain about the safety of these agents and their effect on weight, appetite, and the body’s glycemic response. This article reviews the available research and current recommendations regarding the use of NNSs.
WHAT EFFECT DO NNS s HAVE ON WEIGHT?
The data on NNSs and weight are inconsistent. One randomized controlled trial(RCT) compared weight loss over the course of 1 year (12-week weight loss phase; 9-month weight maintenance phase) when 303 participants consumed either water or drinks sweetened with NNSs.16 Weight loss was significantly greater in the NNS drink group when compared with the water group.16
Observational studies have revealed similar findings.17,18 Data from NHANES revealed that US adults (n = 14,098) during 2 nonconsecutive 24-hour dietary recall periods demonstrated lower total energy (calorie) intake if they consumed NNSs vs no NNSs.19 Another study using 2011-2016 NHANES data on adolescents (n = 7026) found no difference in energy intake between those who consumed beverages containing NNSs vs those who consumed beverages containing sugar.20
Continue to: Other lines of investigation...
Other lines of investigation, including animal studies, have shown that long-term use of NNSs is associated with numerous metabolic derangements including weight gain.21 The negative effects of NNSs appear to be the greatest in males and those who are obese and have high-calorie diets.21
A 2017 meta-analysis concluded that evidence from RCTs does not support a benefit of NNSs on weight management, and that routine consumption of NNSs may be associated with increased body mass index (BMI) and cardiometabolic risk.22 Another systematic review and meta-analysis found that there was a higher pooled risk for obesity among those who drank beverages containing NNSs vs those who drank sugar-containing beverages.23
Based on the most current literature, we conclude that NNSs are not beneficial for weight loss. While there is concern about weight gain through psychological effects (stimulation of sweetness receptors without satiety), further well-designed research is needed to explore whether this concern has merit.
WHAT IS THE EFFECT OF NNSs ON APPETITE?
There appears to be no effect. While original studies seemed to indicate there was an effect, later studies leaned to the contrary.
The notion that NNSs might enhance appetite and food intake was advanced in the 1980s by John Blundell and his research team.24 The hypothesis was that since NNSs uncouple sweet taste and calories, they do not exert the normal post-ingestive inhibitory influence that real sugar does. This, in turn, disrupts appetite control mechanisms.25-27
Continue to: However, subsequent research studies...
However, subsequent research studies found no relationship between the use of NNSs and appetite.28-30 Mattes and colleagues hypothesized that such a difference in findings could result from the fact that earlier studies focused on isolating NNSs from other energy-yielding products, which emphasized an association with heightened hunger.29 Subsequent studies showed that when NNSs were incorporated into energy-yielding products, there was no association between NNSs and increased hunger or appetite.
DO NNSs INCREASE THE RISK FOR TYPE 2 DIABETES MELLITUS?
The data are mixed. One study of women participating in the Nurses’ Health Study II showed that those who consumed caffeinated, artificially-sweetened beverages had a 35% higher risk of developing type 2 diabetes mellitus (T2DM); however, this risk was no longer significant after adjusting for BMI and energy intake.31
The Health Professionals Follow-Up Trial studied more than 40,000 men for more than 20 years and found that NNS consumption increased the risk of developing T2DM by 40%.32 However, this finding lost statistical significance after adjusting for BMI.32
These results make it difficult to determine whether there is any association between NNSs and T2DM; rather NNS-containing beverages are likely consumed more often by those who have higher BMIs and by those trying to lose weight.
A 2017 randomized crossover study involving 10 healthy men looked at the effects of a variety of caloric and non-caloric sweeteners on 24-hour glucose profiles and found no differences.33 Another study, a randomized, double-blind, crossover trial involving 60 non-obese adults without diabetes who did not consume NNSs, randomized the participants one-to-one to drink either 2 cans per day of either a beverage containing aspartame and acesulfame K or an unsweetened, no-calorie beverage for 12 weeks.34
Continue to: After a 4-week washout period...
After a 4-week washout period, the participants then switched to the opposite beverage for 12 weeks. The study concluded that consumption of 2 cans of a beverage containing aspartame and acesulfame K over 12 weeks had no significant effect on insulin sensitivity or secretion in nondiabetic adults.34
Similar results were obtained from a study involving 100 non-obese adults.35 The researchers found that aspartame ingested at 2 different doses (350 or 1050 mg/d) in beverages over 12 weeks had no effect on a 240-minute oral glucose tolerance test, blood pressure, appetite, or body weight.35
A 2016 systematic review critically evaluated the effect of NNSs on both glucose absorption and appetite.36 The review included 14 observational prospective trials, 28 RCTs, and 2 meta-analyses. The sweeteners studied included aspartame, sucralose, saccharin, acesulfame K, and stevia.36 The studies were focused largely on single-exposure outcomes (20 trials), but a minority of the studies (8 trials) looked at longer exposures from 1 to 18 weeks. Only some of the studies controlled for critical variables, such as BMI. In the end, there was no consistent pattern of increased or decreased risk for insulin resistance or diabetes.36
Two meta-analyses tried to determine if an association exists between consumption of beverages containing NNSs and the development of T2DM.37,38 The first meta-analysis with 4 studies showed a slight, but significant, relative risk (RR) of 1.13 (95% confidence interval [CI], 1.02-1.25) for those who consumed beverages containing NNSs.37 In the second meta-analysis (10 studies), NNS consumption had an RR of 1.48 (95% CI, 1.35-1.62), but the risk was lower (and no longer significant) after adjusting for BMI.38 A study of 98 Hispanic adolescents who were overweight or obese found that chronic users (n = 9) of NNSs had higher HbA1c levels 1 year later than did controls (n = 75) and people who initiated use of NNSs between the baseline and 1-year visit (n = 14).39
The American Diabetes Association (ADA) and American Heart Association joint position statement on NNSs, first published in 2012, says that NNSs can be utilized to reduce caloric and carbohydrate consumption for overall diabetes control and to obtain a healthy body weight.40 These principles were reaffirmed in the ADA Standards of Care in 2019.41
Continue to: The 2015 US Scientific Reports on Dietary Guidelines...
The 2015 US Scientific Reports on Dietary Guidelines provided a consensus statement saying, “Future experimental studies should examine the relationship between artificially sweetened soft drinks and biomarkers of insulin resistance and other diabetes markers.”42
DO NNSs HAVE ANY ADVERSE HEALTH EFFECTS?
Maybe. Many individuals avoid NNSs due to fear of developing cancer. While rat studies have previously shown a dose-dependent increased risk of developing cancer, epidemiologic studies in humans have not confirmed an association.43 The National Cancer Institute reports that carcinogenicity studies of NNSs have not shown an association with cancer in humans.44
A prospective study—the Nurses’ Health Study, which followed over 88,000 women for 24 years—found that consumption of > 2 diet sodas per day was associated with an increased risk for coronary heart disease (CHD) and chronic kidney disease (CKD) compared with consumption of < 1 diet soda per month.45 However, other prospective studies have shown that these specific negative health effects may not be present when controlling for weight.45,46
While the prospective studies found some associations between medical conditions (eg, CHD and CKD) and NNS consumption, the literature is limited to intake from beverages and does not include NNS-containing foods. More studies are needed to determine the relationship between NNSs and potential adverse health events, since the current literature is observational and cannot predict causation.
A 2019 study explored the associations between long-term consumption of sugar-sweetened beverages and artificially sweetened beverages (ASBs) and the risk of mortality in the United States.47 This study included 37,716 men from the Health Professionals Follow-up Study and 80,647 women from the Nurses’ Health Study. Subjects who had the highest consumption of ASBs had higher risks for total and cardiovascular disease mortality.47 Cohort-specific analyses showed that an association between ASB consumption and mortality was observed in the participants from the Nurses’ Health Study but not in those from the Health Professionals Follow-up Study, warranting further investigation.47 Cancer mortality and ASB consumption were not shown to have an association in this study.
Continue to: WHY ARE THE DATA INCONCLUSIVE?
WHY ARE THE DATA INCONCLUSIVE?
Nutritional studies are hard to complete accurately outside of the laboratory setting. Also, the science of NNSs is new and evolving.
With regard to obesity and NNSs, it is possible that findings have been due to reverse causation. People who are overweight or obese are more likely to consume low-calorie foods and beverages; they are also at greater risk for developing diseases, such as T2DM.48,49
HOW SAFE ARE NNSs?
They appear to be safe, but more data are needed. Each of the 7 FDA-approved NNSs has passed extensive laboratory, animal, and human testing, and appears to cause no harm in the human body when consumed.49 But clearly the data are incomplete. As we continue to gain a greater understanding of the metabolism of NNSs, we may need to revisit the issue of safety.
ARE THERE ANY NNSs THAT SOME PEOPLE SHOULD AVOID?
Yes. People with phenylketonuria, who have difficulty metabolizing phenylalanine (a component of aspartame), should avoid consumption of aspartame.50
In addition, NNSs have been found to be present in breast milk.51 While the significance of this finding is yet to be determined, we warn against the use of NNSs by women who are breastfeeding.51
WHAT EFFECT—IF ANY—DO NNSs HAVE ON GUT MICROBIOTA?
We don’t know. Disruptions in the gut microbiome have been linked to numerous metabolic abnormalities, including obesity, insulin resistance, and diabetes, as well as cardiovascular disorders.52,53 Diet is a main determinant of balance in the gut microbiota.54 The gut microbiota are centrally involved in energy harvest, and studies have suggested that low gut bacterial diversity is associated with increased adiposity, insulin resistance, and low-grade inflammation.55-60 Whether NNSs have a relationship with abnormal changes in gut microbiota requires further study.
CORRESPONDENCE
Clipper F. Young, PharmD, MPH, CDE, BC-ADM, BCGP, Touro University California, College of Osteopathic Medicine, 1310 Club Drive, Vallejo, CA 94592; Clipper.young@tu.edu.
1. Adult obesity facts. Centers for Disease Control and Prevention Web site. https://www.cdc.gov/obesity/data/adult.html. Reviewed August 13, 2018. Accessed July 15, 2019.
2. Dietary guidelines for Americans 2015-2020: answers to your questions. USDA ChooseMyPlate.gov Web site. https://www.choosemyplate.gov/2015-2020-dietary-guidelines-answers-your-questions. Accessed July 15, 2019.
3. Additional information about high-intensity sweeteners permitted for use in food in the United States. US Food and Drug Administration Web site. https://www.fda.gov/food/food-additives-petitions/additional-information-about-high-intensity-sweeteners-permitted-use-food-united-states. Published February 8, 2018. Accessed July 15, 2019.
4. Magnuson B, for the Aspartame Expert Work Group. Nutritive and non-nutritive sweeteners. NNNS: aspartame, methanol and formaldehyde relationships (2011). https://www.foodsweeteners.com/wp-content/uploads/2015/08/Aspartame-Methanol-and-Formaldehyde-Relationships.pdf. Accessed July 15, 2019.
5. Jo JH, Kim S, Jeon TW, et al. Investigation of the regulatory effects of saccharin on cytochrome P450s in male ICR mice. Toxicol Res. 2017;33:25-30.
6. Shwide-Slavin C, Swift C, Ross T. Nonnutritive sweetener: where are we today? Diabetes Spectrum. 2012;25:104-110.
7. Chattopadhyay S, Raychaudhuri U, Chakraborty R. Artificial sweeteners – a review. J Food Sci Technol. 2014;51:611-621.
8. EFSA Panel on Food Additives and Nutrient Sources added to Food. Scientific opinion on the safety of advantame for the proposed uses as a food additive. EFSA Journal. 2013;11:3301.
9. Fitch C, Keim KS; Academy of Nutrition and Dietetics. Position of the Academy of Nutrition and Dietetics: use of nutritive and nonnutritive sweeteners. J Acad Nutr Diet. 2012;112:739-758.
10. Ng SW, Slining MM, Popkin BM. Use of caloric and non-caloric sweeteners in US consumer packaged foods, 2005-2009. J Acad Nutr Diet. 2012;112:1828-1834.
11. Sylvetsky AC, Rother KI. Trends in the consumption of low-calorie sweeteners. Physiol Behav. 2016;164(Pt B):446-450.
12. Piernas C, Ng SW, Popkin B. Trends in purchases and intake of foods and beverages containing caloric and low-calorie sweeteners over the last decade in the United States. Pediatr Obes. 2013;8:294-306.
13. Sylvetsky AC, Welsh JA, Brown RJ, et al. Low-calorie sweetener consumption is increasing in the United States. Am J Clin Nutr. 2012;96:640-646.
14. Bleich SN, Wolfson JA, Vine S, et al. Diet-beverage consumption and caloric intake among US adults, overall and by body weight. Am J Public Health. 2014;104:e72-e78.
15. Drewnowski A, Rehm CD. Socio-demographic correlates and trends in low-calorie sweetener use among adults in the United States from 1999 to 2008. Eur J Clin Nutr. 2015;69:1035-1041.
16. Peters JC, Wyatt HR, Foster GD, et al. The effects of water and non-nutritive sweetened beverages on weight loss during a 12-week weight loss treatment program. Obesity 2014;22:1415-1421.
17. Peters JC, Wyatt HR, Foster GD, et al. The effects of water and non-nutritive sweetened beverages on weight loss during a 12-week weight loss treatment program. Obesity (Silver Spring). 2014;22:1415-1421.
18. Bellisle F, Drewnowski A. Intense sweeteners, energy intake and the control of body weight. Eur J Clin Nutr. 2007;61:691-700.
19. Malek AM, Hunt KJ, DellaValle DM, et al. Reported consumption of low-calorie sweetener in foods, beverages, and food and beverage additions by US adults: NHANES 2007-2012. Curr Dev Nutr. 2018;2:nzy054.
20. Sylvetsky AC, Figueroa J, Zimmerman T, et al. Consumption of low-calorie sweetened beverages is associated with higher total energy and sugar intake among children, NHANES 2011-2016. Pediatr Obes. 2019;2:e12535.
21. Fowler SPG. Low-calorie sweetener use and energy balance: results from experimental studies in animals, and large-scale prospective studies in humans. Physiol Behav. 2016;164(Pt B):517-523.
22. Azad MB, Abou-Setta AM, Chauhan BF, et al. Nonnutritive sweeteners and cardiometabolic health: a systematic review and meta-analysis of randomized controlled trials and prospective cohort studies. CMAJ. 2017;189: E929-E939.
23. Ruanpeng D, Thongprayoon C, Cheungpasitporn W, et al. Sugar and artificially-sweetened beverages linked to obesity: a systematic review and meta-analysis. QJM. 2017;110:513-520.
24. Blundell JE, Rogers PJ, Hill AJ. Uncoupling sweetness and calories: methodological aspects of laboratory studies on appetite control. Appetite. 1988;11(Suppl 1):54-61.
25. Bellisle F. Intense sweeteners, appetite for the sweet taste, and relationship to weight management. Curr Obes Rep. 2015;4:106-110.
26. Bryant CE, Wasse LK, Astbury N, et al. Non-nutritive sweeteners: no class effect on the glycaemic or appetite responses to ingested glucose. Eur J Clin Nutr. 2014;68:629-631.
27. Canty DJ, Chan MM. Effects of consumption of caloric vs noncaloric sweet drinks on indices of hunger and food consumption in normal adults. Am J Clin Nutr. 1991;53:1159-1164.
28. Meyer-Gerspach AC, Wolnerhanssen B, Beglinger C. Functional roles of low calorie sweeteners on gut function. Physiol Behav. 2016;164(Pt B):479-481.
29. Mattes RD, Popkin BM. Nonnutritive sweetener consumption in humans: effects on appetite and food intake and their putative mechanisms. Am J Clin Nutr. 2009;89:1-14.
30. Bhupathiraju SN, Pan A, Malik VS, et al. Caffeinated and caffeine-free beverages and risk of type 2 diabetes. Am J Clin Nutr. 2013;97:155-166.
31. Schulze MB, Manson JE, Ludwig DS, et al. Sugar-sweetened beverages, weight gain, and incidence of type 2 diabetes in young and middle-aged women. JAMA. 2004;292:927-934.
32. de Koning L, Malik VS, Rimm EB, et al. Sugar-sweetened and artificially sweetened beverage consumption and the risk of type 2 diabetes in men. Am J Clin Nutr. 2011;93:1321-1327.
33. Tey SL, Salleh NB, Henry CJ, et al. Effect of non-nutritive (artificial vs natural) sweeteners on 24-hour glucose profile. Eur J Clin Nutr. 2017;71:1129-1132.
34. Bonnet F, Tavenard A, Esvan M, et al. Consumption of a carbonated beverage with high-intensity sweeteners has no effect on insulin sensitivity and secretion in nondiabetic adults. J Nutr. 2018;148:1293-1299.
35. Higgins KA, Considine RV, Mattes RD. Aspartame consumption for 12 weeks does not affect glycemia, appetite, or body weight of healthy, lean adults in a randomized controlled trial. J Nutr. 2018;148:650-657.
36. Romo-Romo A, Aguilar-Salinas CA, Brito-Cordova GX, et al. Effects of the non-nutritive sweeteners on glucose metabolism and appetite regulating hormones: systematic review of observational prospective studies and clinical trials. PloS One. 2016;11:e0161264.
37. Greenwood DC, Threspleton DE, Evans CE, et al. Association between sugar-sweetened and artificially sweetened soft drinks and type 2 diabetes: systematic review and dose-response meta-analysis of prospective studies. Br J Nutr. 2014;112:725-734.
38. Imamura F, O’Conner L, Ye M, et al. Consumption of sugar sweetened beverages, artificially sweetened beverages, and fruit juice and incidence of type 2 diabetes: systematic review, meta-analysis, and estimation of population attributable fraction. BMJ. 2015;351:h3576.
39. Davis JN, Asigbee FM, Markowitz AK, et al. Consumption of artificial sweetened beverages associated with adiposity and increasing HbA1c in Hispanic youth. Clin Obes. 2018;8:236-243.
40. Gardner C, Wylie-Rosett J, Gidding SS, et al. Nonnutritive sweeteners: current use and health perspectives. a scientific statement from the American Heart Association and the American Diabetes Association. Diabetes Care. 2012;35:1798-1808.
41. American Diabetes Association. Standards of Medical Care in Diabetes—2019. Diabetes Care. 2019;42(Suppl 1):S1-S183.
42. Dietary Guidelines Advisory Committee. Scientific Report of the 2015 Dietary Guidelines Advisory Committee: advisory report to the Secretary of Health and Human Services and the Secretary of Agriculture. Office of Disease Prevention and Health Promotion Web site. https://health.gov/dietaryguidelines/2015-scientific-report/.Published February 2015. Accessed July 15, 2019.
43. Aune D. Soft drinks, aspartame, and the risk of cancer and cardiovascular disease. Am J Clin Nutr. 2012;96:1249-1251.
44. Artificial sweeteners and cancer. National Cancer Institute Web site. https://www.cancer.gov/about-cancer/causes-prevention/risk/diet/artificial-sweeteners-fact-sheet. Reviewed August 10, 2016. Accessed July 15, 2019.
45. Fung TT, Malik V, Rexrode KM, et al. Sweetened beverage consumption and risk of coronary heart disease in women. Am J Clin Nutr. 2009;89:1037-1042.
46. Lin J, Curhan GC. Associations of sugar and artificially sweetened soda with albuminuria and kidney function decline in women. Clin J Am Soc Nephrol. 2011;6:160-166.
47. Malik VS, Li Y, Pan A, et al. Long-term consumption of sugar-sweetened and artificially sweetened beverages and risk of mortality in US adults. Circulation. 2019;139:2113-2125.
48. Gardener H, Rundek T, Markert M, et al. Diet soft drink consumption is associated with an increased risk of vascular events in the Northern Manhattan Study. J Gen Inten Med. 2012;27:1120-1126.
49. Fitch C, Keim KS. Position of the Academy of Nutrition and Dietetics: use of nutritive and nonnutritive sweeteners. J Acad Nutr Diet. 2012;112:739-758.
50. US Food and Drug Administration. Additional information about high-intensity sweeteners permitted for use in food in the United States. https://www.fda.gov/food/ingredientspackaginglabeling/foodadditivesingredients/ucm397725.htm#Aspartame. Accessed May 26, 2019.
51. Sylvetsky AC, Gardner AL, Bauman V, et al. Nonnutritive sweeteners in breast milk. J Toxicol Environ Health. 2015;78:1029-1032.
52. Rajani C, Jia W. Disruptions in gut microbial-host co-metabolism and the development of metabolic disorders. Clin Sci (Lond). 2018;132:791-811.
53. Kho ZY, Lal SK. The human gut microbiome—a potential controller of wellness and disease. Front Microbiol. 2018;9:1835.
54. Nettleton JE, Reimer RA, Shearer J. Reshaping the gut microbiota: impact of low calorie sweeteners and the link to insulin resistance. Physiol Behav. 2016;164(Pt B):488-493.
55. Turnbaugh PJ, Hamady M, Yatsunenko T, et al. A core gut microbiome in obese and lean twins. Nature. 2009;457:480-484.
56. Cotillard A, Kennedy SP, Kong LC, et al. Dietary intervention impact on gut microbial gene richness. Nature. 2013;500:585-588.
57. Le Chatelier E, Nielsen T, Qin J, et al. Richness of human gut microbiome correlates with metabolic markers. Nature. 2013;500:541-546.
58. Abou-Donia MB, El-Masry EM, Abdel-Rahman AA, et al. Splenda alters gut microflora and increases intestinal p-glycoprotein and cytochrome P-450 in male rats. J Toxicol Environ Health A. 2008;71:1415-1429.
59. Anderson RL. Effect of saccharin ingestion on stool composition in relation to caecal enlargement and increased stool hydration. Food Chem Toxicol. 1983;21:255-257.
60. Suez J, Korem T, Zeevi D, et al. Artificial sweeteners induce glucose intolerance by altering the gut microbiota. Nature. 2014;514:181-186.
An estimated 93.3 million Americans (roughly 40% of the US population) were obese in 2015-2016, and most of them had at least 1 chronic disease.1 As a result, patient education focused on lifestyle modification, including healthy nutrition and physical activity, has become an integral part of our everyday practice.
At the same time, the most recent dietary guidelines recommend that added sugar make up < 10% of daily calories.2 In the United States, low-calorie food and beverages containing non-nutritive sweeteners (NNSs; TABLE3-8) have become a popular means of keeping the sweetness in our diet without the health ramifications associated with sugar. These NNSs (aka, artificial sweeteners, high-intensity sweeteners, and non-caloric sweeteners) are ubiquitous in soft drinks, processed grains (including breads, cereals, and granola bars), and dairy products (including yogurts, flavored milk, and ice cream). As examples, NNSs are present in 42% of flavored waters, 33% of yogurts, and all diet beverages.9,10 They can even be found in medications, multivitamins, toothpaste, and mouthwash.
Business is booming
Global NNS consumption has been growing more than 5% per year, meaning that by 2020, NNSs are expected to be a $2.2 billion industry.11 One study using data from the National Health and Nutrition Examination Survey (NHANES) found that the use of NNSs in the United States increased from 21.1% in 2003 to 24.9% in 2009-2010 among adults and increased from 7.8% to 18.9% over the same time period among children.12
The main increase in the consumption of NNSs across all age groups has been via the consumption of beverages. Approximately 11% of healthy weight, 19% of overweight, and 22% of obese adults consume diet beverages.13,14 Consumption of diet beverages or NNSs increases with age12 and is especially common among women with higher levels of education and income.15
However, concerns remain about the safety of these agents and their effect on weight, appetite, and the body’s glycemic response. This article reviews the available research and current recommendations regarding the use of NNSs.
WHAT EFFECT DO NNS s HAVE ON WEIGHT?
The data on NNSs and weight are inconsistent. One randomized controlled trial(RCT) compared weight loss over the course of 1 year (12-week weight loss phase; 9-month weight maintenance phase) when 303 participants consumed either water or drinks sweetened with NNSs.16 Weight loss was significantly greater in the NNS drink group when compared with the water group.16
Observational studies have revealed similar findings.17,18 Data from NHANES revealed that US adults (n = 14,098) during 2 nonconsecutive 24-hour dietary recall periods demonstrated lower total energy (calorie) intake if they consumed NNSs vs no NNSs.19 Another study using 2011-2016 NHANES data on adolescents (n = 7026) found no difference in energy intake between those who consumed beverages containing NNSs vs those who consumed beverages containing sugar.20
Continue to: Other lines of investigation...
Other lines of investigation, including animal studies, have shown that long-term use of NNSs is associated with numerous metabolic derangements including weight gain.21 The negative effects of NNSs appear to be the greatest in males and those who are obese and have high-calorie diets.21
A 2017 meta-analysis concluded that evidence from RCTs does not support a benefit of NNSs on weight management, and that routine consumption of NNSs may be associated with increased body mass index (BMI) and cardiometabolic risk.22 Another systematic review and meta-analysis found that there was a higher pooled risk for obesity among those who drank beverages containing NNSs vs those who drank sugar-containing beverages.23
Based on the most current literature, we conclude that NNSs are not beneficial for weight loss. While there is concern about weight gain through psychological effects (stimulation of sweetness receptors without satiety), further well-designed research is needed to explore whether this concern has merit.
WHAT IS THE EFFECT OF NNSs ON APPETITE?
There appears to be no effect. While original studies seemed to indicate there was an effect, later studies leaned to the contrary.
The notion that NNSs might enhance appetite and food intake was advanced in the 1980s by John Blundell and his research team.24 The hypothesis was that since NNSs uncouple sweet taste and calories, they do not exert the normal post-ingestive inhibitory influence that real sugar does. This, in turn, disrupts appetite control mechanisms.25-27
Continue to: However, subsequent research studies...
However, subsequent research studies found no relationship between the use of NNSs and appetite.28-30 Mattes and colleagues hypothesized that such a difference in findings could result from the fact that earlier studies focused on isolating NNSs from other energy-yielding products, which emphasized an association with heightened hunger.29 Subsequent studies showed that when NNSs were incorporated into energy-yielding products, there was no association between NNSs and increased hunger or appetite.
DO NNSs INCREASE THE RISK FOR TYPE 2 DIABETES MELLITUS?
The data are mixed. One study of women participating in the Nurses’ Health Study II showed that those who consumed caffeinated, artificially-sweetened beverages had a 35% higher risk of developing type 2 diabetes mellitus (T2DM); however, this risk was no longer significant after adjusting for BMI and energy intake.31
The Health Professionals Follow-Up Trial studied more than 40,000 men for more than 20 years and found that NNS consumption increased the risk of developing T2DM by 40%.32 However, this finding lost statistical significance after adjusting for BMI.32
These results make it difficult to determine whether there is any association between NNSs and T2DM; rather NNS-containing beverages are likely consumed more often by those who have higher BMIs and by those trying to lose weight.
A 2017 randomized crossover study involving 10 healthy men looked at the effects of a variety of caloric and non-caloric sweeteners on 24-hour glucose profiles and found no differences.33 Another study, a randomized, double-blind, crossover trial involving 60 non-obese adults without diabetes who did not consume NNSs, randomized the participants one-to-one to drink either 2 cans per day of either a beverage containing aspartame and acesulfame K or an unsweetened, no-calorie beverage for 12 weeks.34
Continue to: After a 4-week washout period...
After a 4-week washout period, the participants then switched to the opposite beverage for 12 weeks. The study concluded that consumption of 2 cans of a beverage containing aspartame and acesulfame K over 12 weeks had no significant effect on insulin sensitivity or secretion in nondiabetic adults.34
Similar results were obtained from a study involving 100 non-obese adults.35 The researchers found that aspartame ingested at 2 different doses (350 or 1050 mg/d) in beverages over 12 weeks had no effect on a 240-minute oral glucose tolerance test, blood pressure, appetite, or body weight.35
A 2016 systematic review critically evaluated the effect of NNSs on both glucose absorption and appetite.36 The review included 14 observational prospective trials, 28 RCTs, and 2 meta-analyses. The sweeteners studied included aspartame, sucralose, saccharin, acesulfame K, and stevia.36 The studies were focused largely on single-exposure outcomes (20 trials), but a minority of the studies (8 trials) looked at longer exposures from 1 to 18 weeks. Only some of the studies controlled for critical variables, such as BMI. In the end, there was no consistent pattern of increased or decreased risk for insulin resistance or diabetes.36
Two meta-analyses tried to determine if an association exists between consumption of beverages containing NNSs and the development of T2DM.37,38 The first meta-analysis with 4 studies showed a slight, but significant, relative risk (RR) of 1.13 (95% confidence interval [CI], 1.02-1.25) for those who consumed beverages containing NNSs.37 In the second meta-analysis (10 studies), NNS consumption had an RR of 1.48 (95% CI, 1.35-1.62), but the risk was lower (and no longer significant) after adjusting for BMI.38 A study of 98 Hispanic adolescents who were overweight or obese found that chronic users (n = 9) of NNSs had higher HbA1c levels 1 year later than did controls (n = 75) and people who initiated use of NNSs between the baseline and 1-year visit (n = 14).39
The American Diabetes Association (ADA) and American Heart Association joint position statement on NNSs, first published in 2012, says that NNSs can be utilized to reduce caloric and carbohydrate consumption for overall diabetes control and to obtain a healthy body weight.40 These principles were reaffirmed in the ADA Standards of Care in 2019.41
Continue to: The 2015 US Scientific Reports on Dietary Guidelines...
The 2015 US Scientific Reports on Dietary Guidelines provided a consensus statement saying, “Future experimental studies should examine the relationship between artificially sweetened soft drinks and biomarkers of insulin resistance and other diabetes markers.”42
DO NNSs HAVE ANY ADVERSE HEALTH EFFECTS?
Maybe. Many individuals avoid NNSs due to fear of developing cancer. While rat studies have previously shown a dose-dependent increased risk of developing cancer, epidemiologic studies in humans have not confirmed an association.43 The National Cancer Institute reports that carcinogenicity studies of NNSs have not shown an association with cancer in humans.44
A prospective study—the Nurses’ Health Study, which followed over 88,000 women for 24 years—found that consumption of > 2 diet sodas per day was associated with an increased risk for coronary heart disease (CHD) and chronic kidney disease (CKD) compared with consumption of < 1 diet soda per month.45 However, other prospective studies have shown that these specific negative health effects may not be present when controlling for weight.45,46
While the prospective studies found some associations between medical conditions (eg, CHD and CKD) and NNS consumption, the literature is limited to intake from beverages and does not include NNS-containing foods. More studies are needed to determine the relationship between NNSs and potential adverse health events, since the current literature is observational and cannot predict causation.
A 2019 study explored the associations between long-term consumption of sugar-sweetened beverages and artificially sweetened beverages (ASBs) and the risk of mortality in the United States.47 This study included 37,716 men from the Health Professionals Follow-up Study and 80,647 women from the Nurses’ Health Study. Subjects who had the highest consumption of ASBs had higher risks for total and cardiovascular disease mortality.47 Cohort-specific analyses showed that an association between ASB consumption and mortality was observed in the participants from the Nurses’ Health Study but not in those from the Health Professionals Follow-up Study, warranting further investigation.47 Cancer mortality and ASB consumption were not shown to have an association in this study.
Continue to: WHY ARE THE DATA INCONCLUSIVE?
WHY ARE THE DATA INCONCLUSIVE?
Nutritional studies are hard to complete accurately outside of the laboratory setting. Also, the science of NNSs is new and evolving.
With regard to obesity and NNSs, it is possible that findings have been due to reverse causation. People who are overweight or obese are more likely to consume low-calorie foods and beverages; they are also at greater risk for developing diseases, such as T2DM.48,49
HOW SAFE ARE NNSs?
They appear to be safe, but more data are needed. Each of the 7 FDA-approved NNSs has passed extensive laboratory, animal, and human testing, and appears to cause no harm in the human body when consumed.49 But clearly the data are incomplete. As we continue to gain a greater understanding of the metabolism of NNSs, we may need to revisit the issue of safety.
ARE THERE ANY NNSs THAT SOME PEOPLE SHOULD AVOID?
Yes. People with phenylketonuria, who have difficulty metabolizing phenylalanine (a component of aspartame), should avoid consumption of aspartame.50
In addition, NNSs have been found to be present in breast milk.51 While the significance of this finding is yet to be determined, we warn against the use of NNSs by women who are breastfeeding.51
WHAT EFFECT—IF ANY—DO NNSs HAVE ON GUT MICROBIOTA?
We don’t know. Disruptions in the gut microbiome have been linked to numerous metabolic abnormalities, including obesity, insulin resistance, and diabetes, as well as cardiovascular disorders.52,53 Diet is a main determinant of balance in the gut microbiota.54 The gut microbiota are centrally involved in energy harvest, and studies have suggested that low gut bacterial diversity is associated with increased adiposity, insulin resistance, and low-grade inflammation.55-60 Whether NNSs have a relationship with abnormal changes in gut microbiota requires further study.
CORRESPONDENCE
Clipper F. Young, PharmD, MPH, CDE, BC-ADM, BCGP, Touro University California, College of Osteopathic Medicine, 1310 Club Drive, Vallejo, CA 94592; Clipper.young@tu.edu.
An estimated 93.3 million Americans (roughly 40% of the US population) were obese in 2015-2016, and most of them had at least 1 chronic disease.1 As a result, patient education focused on lifestyle modification, including healthy nutrition and physical activity, has become an integral part of our everyday practice.
At the same time, the most recent dietary guidelines recommend that added sugar make up < 10% of daily calories.2 In the United States, low-calorie food and beverages containing non-nutritive sweeteners (NNSs; TABLE3-8) have become a popular means of keeping the sweetness in our diet without the health ramifications associated with sugar. These NNSs (aka, artificial sweeteners, high-intensity sweeteners, and non-caloric sweeteners) are ubiquitous in soft drinks, processed grains (including breads, cereals, and granola bars), and dairy products (including yogurts, flavored milk, and ice cream). As examples, NNSs are present in 42% of flavored waters, 33% of yogurts, and all diet beverages.9,10 They can even be found in medications, multivitamins, toothpaste, and mouthwash.
Business is booming
Global NNS consumption has been growing more than 5% per year, meaning that by 2020, NNSs are expected to be a $2.2 billion industry.11 One study using data from the National Health and Nutrition Examination Survey (NHANES) found that the use of NNSs in the United States increased from 21.1% in 2003 to 24.9% in 2009-2010 among adults and increased from 7.8% to 18.9% over the same time period among children.12
The main increase in the consumption of NNSs across all age groups has been via the consumption of beverages. Approximately 11% of healthy weight, 19% of overweight, and 22% of obese adults consume diet beverages.13,14 Consumption of diet beverages or NNSs increases with age12 and is especially common among women with higher levels of education and income.15
However, concerns remain about the safety of these agents and their effect on weight, appetite, and the body’s glycemic response. This article reviews the available research and current recommendations regarding the use of NNSs.
WHAT EFFECT DO NNS s HAVE ON WEIGHT?
The data on NNSs and weight are inconsistent. One randomized controlled trial(RCT) compared weight loss over the course of 1 year (12-week weight loss phase; 9-month weight maintenance phase) when 303 participants consumed either water or drinks sweetened with NNSs.16 Weight loss was significantly greater in the NNS drink group when compared with the water group.16
Observational studies have revealed similar findings.17,18 Data from NHANES revealed that US adults (n = 14,098) during 2 nonconsecutive 24-hour dietary recall periods demonstrated lower total energy (calorie) intake if they consumed NNSs vs no NNSs.19 Another study using 2011-2016 NHANES data on adolescents (n = 7026) found no difference in energy intake between those who consumed beverages containing NNSs vs those who consumed beverages containing sugar.20
Continue to: Other lines of investigation...
Other lines of investigation, including animal studies, have shown that long-term use of NNSs is associated with numerous metabolic derangements including weight gain.21 The negative effects of NNSs appear to be the greatest in males and those who are obese and have high-calorie diets.21
A 2017 meta-analysis concluded that evidence from RCTs does not support a benefit of NNSs on weight management, and that routine consumption of NNSs may be associated with increased body mass index (BMI) and cardiometabolic risk.22 Another systematic review and meta-analysis found that there was a higher pooled risk for obesity among those who drank beverages containing NNSs vs those who drank sugar-containing beverages.23
Based on the most current literature, we conclude that NNSs are not beneficial for weight loss. While there is concern about weight gain through psychological effects (stimulation of sweetness receptors without satiety), further well-designed research is needed to explore whether this concern has merit.
WHAT IS THE EFFECT OF NNSs ON APPETITE?
There appears to be no effect. While original studies seemed to indicate there was an effect, later studies leaned to the contrary.
The notion that NNSs might enhance appetite and food intake was advanced in the 1980s by John Blundell and his research team.24 The hypothesis was that since NNSs uncouple sweet taste and calories, they do not exert the normal post-ingestive inhibitory influence that real sugar does. This, in turn, disrupts appetite control mechanisms.25-27
Continue to: However, subsequent research studies...
However, subsequent research studies found no relationship between the use of NNSs and appetite.28-30 Mattes and colleagues hypothesized that such a difference in findings could result from the fact that earlier studies focused on isolating NNSs from other energy-yielding products, which emphasized an association with heightened hunger.29 Subsequent studies showed that when NNSs were incorporated into energy-yielding products, there was no association between NNSs and increased hunger or appetite.
DO NNSs INCREASE THE RISK FOR TYPE 2 DIABETES MELLITUS?
The data are mixed. One study of women participating in the Nurses’ Health Study II showed that those who consumed caffeinated, artificially-sweetened beverages had a 35% higher risk of developing type 2 diabetes mellitus (T2DM); however, this risk was no longer significant after adjusting for BMI and energy intake.31
The Health Professionals Follow-Up Trial studied more than 40,000 men for more than 20 years and found that NNS consumption increased the risk of developing T2DM by 40%.32 However, this finding lost statistical significance after adjusting for BMI.32
These results make it difficult to determine whether there is any association between NNSs and T2DM; rather NNS-containing beverages are likely consumed more often by those who have higher BMIs and by those trying to lose weight.
A 2017 randomized crossover study involving 10 healthy men looked at the effects of a variety of caloric and non-caloric sweeteners on 24-hour glucose profiles and found no differences.33 Another study, a randomized, double-blind, crossover trial involving 60 non-obese adults without diabetes who did not consume NNSs, randomized the participants one-to-one to drink either 2 cans per day of either a beverage containing aspartame and acesulfame K or an unsweetened, no-calorie beverage for 12 weeks.34
Continue to: After a 4-week washout period...
After a 4-week washout period, the participants then switched to the opposite beverage for 12 weeks. The study concluded that consumption of 2 cans of a beverage containing aspartame and acesulfame K over 12 weeks had no significant effect on insulin sensitivity or secretion in nondiabetic adults.34
Similar results were obtained from a study involving 100 non-obese adults.35 The researchers found that aspartame ingested at 2 different doses (350 or 1050 mg/d) in beverages over 12 weeks had no effect on a 240-minute oral glucose tolerance test, blood pressure, appetite, or body weight.35
A 2016 systematic review critically evaluated the effect of NNSs on both glucose absorption and appetite.36 The review included 14 observational prospective trials, 28 RCTs, and 2 meta-analyses. The sweeteners studied included aspartame, sucralose, saccharin, acesulfame K, and stevia.36 The studies were focused largely on single-exposure outcomes (20 trials), but a minority of the studies (8 trials) looked at longer exposures from 1 to 18 weeks. Only some of the studies controlled for critical variables, such as BMI. In the end, there was no consistent pattern of increased or decreased risk for insulin resistance or diabetes.36
Two meta-analyses tried to determine if an association exists between consumption of beverages containing NNSs and the development of T2DM.37,38 The first meta-analysis with 4 studies showed a slight, but significant, relative risk (RR) of 1.13 (95% confidence interval [CI], 1.02-1.25) for those who consumed beverages containing NNSs.37 In the second meta-analysis (10 studies), NNS consumption had an RR of 1.48 (95% CI, 1.35-1.62), but the risk was lower (and no longer significant) after adjusting for BMI.38 A study of 98 Hispanic adolescents who were overweight or obese found that chronic users (n = 9) of NNSs had higher HbA1c levels 1 year later than did controls (n = 75) and people who initiated use of NNSs between the baseline and 1-year visit (n = 14).39
The American Diabetes Association (ADA) and American Heart Association joint position statement on NNSs, first published in 2012, says that NNSs can be utilized to reduce caloric and carbohydrate consumption for overall diabetes control and to obtain a healthy body weight.40 These principles were reaffirmed in the ADA Standards of Care in 2019.41
Continue to: The 2015 US Scientific Reports on Dietary Guidelines...
The 2015 US Scientific Reports on Dietary Guidelines provided a consensus statement saying, “Future experimental studies should examine the relationship between artificially sweetened soft drinks and biomarkers of insulin resistance and other diabetes markers.”42
DO NNSs HAVE ANY ADVERSE HEALTH EFFECTS?
Maybe. Many individuals avoid NNSs due to fear of developing cancer. While rat studies have previously shown a dose-dependent increased risk of developing cancer, epidemiologic studies in humans have not confirmed an association.43 The National Cancer Institute reports that carcinogenicity studies of NNSs have not shown an association with cancer in humans.44
A prospective study—the Nurses’ Health Study, which followed over 88,000 women for 24 years—found that consumption of > 2 diet sodas per day was associated with an increased risk for coronary heart disease (CHD) and chronic kidney disease (CKD) compared with consumption of < 1 diet soda per month.45 However, other prospective studies have shown that these specific negative health effects may not be present when controlling for weight.45,46
While the prospective studies found some associations between medical conditions (eg, CHD and CKD) and NNS consumption, the literature is limited to intake from beverages and does not include NNS-containing foods. More studies are needed to determine the relationship between NNSs and potential adverse health events, since the current literature is observational and cannot predict causation.
A 2019 study explored the associations between long-term consumption of sugar-sweetened beverages and artificially sweetened beverages (ASBs) and the risk of mortality in the United States.47 This study included 37,716 men from the Health Professionals Follow-up Study and 80,647 women from the Nurses’ Health Study. Subjects who had the highest consumption of ASBs had higher risks for total and cardiovascular disease mortality.47 Cohort-specific analyses showed that an association between ASB consumption and mortality was observed in the participants from the Nurses’ Health Study but not in those from the Health Professionals Follow-up Study, warranting further investigation.47 Cancer mortality and ASB consumption were not shown to have an association in this study.
Continue to: WHY ARE THE DATA INCONCLUSIVE?
WHY ARE THE DATA INCONCLUSIVE?
Nutritional studies are hard to complete accurately outside of the laboratory setting. Also, the science of NNSs is new and evolving.
With regard to obesity and NNSs, it is possible that findings have been due to reverse causation. People who are overweight or obese are more likely to consume low-calorie foods and beverages; they are also at greater risk for developing diseases, such as T2DM.48,49
HOW SAFE ARE NNSs?
They appear to be safe, but more data are needed. Each of the 7 FDA-approved NNSs has passed extensive laboratory, animal, and human testing, and appears to cause no harm in the human body when consumed.49 But clearly the data are incomplete. As we continue to gain a greater understanding of the metabolism of NNSs, we may need to revisit the issue of safety.
ARE THERE ANY NNSs THAT SOME PEOPLE SHOULD AVOID?
Yes. People with phenylketonuria, who have difficulty metabolizing phenylalanine (a component of aspartame), should avoid consumption of aspartame.50
In addition, NNSs have been found to be present in breast milk.51 While the significance of this finding is yet to be determined, we warn against the use of NNSs by women who are breastfeeding.51
WHAT EFFECT—IF ANY—DO NNSs HAVE ON GUT MICROBIOTA?
We don’t know. Disruptions in the gut microbiome have been linked to numerous metabolic abnormalities, including obesity, insulin resistance, and diabetes, as well as cardiovascular disorders.52,53 Diet is a main determinant of balance in the gut microbiota.54 The gut microbiota are centrally involved in energy harvest, and studies have suggested that low gut bacterial diversity is associated with increased adiposity, insulin resistance, and low-grade inflammation.55-60 Whether NNSs have a relationship with abnormal changes in gut microbiota requires further study.
CORRESPONDENCE
Clipper F. Young, PharmD, MPH, CDE, BC-ADM, BCGP, Touro University California, College of Osteopathic Medicine, 1310 Club Drive, Vallejo, CA 94592; Clipper.young@tu.edu.
1. Adult obesity facts. Centers for Disease Control and Prevention Web site. https://www.cdc.gov/obesity/data/adult.html. Reviewed August 13, 2018. Accessed July 15, 2019.
2. Dietary guidelines for Americans 2015-2020: answers to your questions. USDA ChooseMyPlate.gov Web site. https://www.choosemyplate.gov/2015-2020-dietary-guidelines-answers-your-questions. Accessed July 15, 2019.
3. Additional information about high-intensity sweeteners permitted for use in food in the United States. US Food and Drug Administration Web site. https://www.fda.gov/food/food-additives-petitions/additional-information-about-high-intensity-sweeteners-permitted-use-food-united-states. Published February 8, 2018. Accessed July 15, 2019.
4. Magnuson B, for the Aspartame Expert Work Group. Nutritive and non-nutritive sweeteners. NNNS: aspartame, methanol and formaldehyde relationships (2011). https://www.foodsweeteners.com/wp-content/uploads/2015/08/Aspartame-Methanol-and-Formaldehyde-Relationships.pdf. Accessed July 15, 2019.
5. Jo JH, Kim S, Jeon TW, et al. Investigation of the regulatory effects of saccharin on cytochrome P450s in male ICR mice. Toxicol Res. 2017;33:25-30.
6. Shwide-Slavin C, Swift C, Ross T. Nonnutritive sweetener: where are we today? Diabetes Spectrum. 2012;25:104-110.
7. Chattopadhyay S, Raychaudhuri U, Chakraborty R. Artificial sweeteners – a review. J Food Sci Technol. 2014;51:611-621.
8. EFSA Panel on Food Additives and Nutrient Sources added to Food. Scientific opinion on the safety of advantame for the proposed uses as a food additive. EFSA Journal. 2013;11:3301.
9. Fitch C, Keim KS; Academy of Nutrition and Dietetics. Position of the Academy of Nutrition and Dietetics: use of nutritive and nonnutritive sweeteners. J Acad Nutr Diet. 2012;112:739-758.
10. Ng SW, Slining MM, Popkin BM. Use of caloric and non-caloric sweeteners in US consumer packaged foods, 2005-2009. J Acad Nutr Diet. 2012;112:1828-1834.
11. Sylvetsky AC, Rother KI. Trends in the consumption of low-calorie sweeteners. Physiol Behav. 2016;164(Pt B):446-450.
12. Piernas C, Ng SW, Popkin B. Trends in purchases and intake of foods and beverages containing caloric and low-calorie sweeteners over the last decade in the United States. Pediatr Obes. 2013;8:294-306.
13. Sylvetsky AC, Welsh JA, Brown RJ, et al. Low-calorie sweetener consumption is increasing in the United States. Am J Clin Nutr. 2012;96:640-646.
14. Bleich SN, Wolfson JA, Vine S, et al. Diet-beverage consumption and caloric intake among US adults, overall and by body weight. Am J Public Health. 2014;104:e72-e78.
15. Drewnowski A, Rehm CD. Socio-demographic correlates and trends in low-calorie sweetener use among adults in the United States from 1999 to 2008. Eur J Clin Nutr. 2015;69:1035-1041.
16. Peters JC, Wyatt HR, Foster GD, et al. The effects of water and non-nutritive sweetened beverages on weight loss during a 12-week weight loss treatment program. Obesity 2014;22:1415-1421.
17. Peters JC, Wyatt HR, Foster GD, et al. The effects of water and non-nutritive sweetened beverages on weight loss during a 12-week weight loss treatment program. Obesity (Silver Spring). 2014;22:1415-1421.
18. Bellisle F, Drewnowski A. Intense sweeteners, energy intake and the control of body weight. Eur J Clin Nutr. 2007;61:691-700.
19. Malek AM, Hunt KJ, DellaValle DM, et al. Reported consumption of low-calorie sweetener in foods, beverages, and food and beverage additions by US adults: NHANES 2007-2012. Curr Dev Nutr. 2018;2:nzy054.
20. Sylvetsky AC, Figueroa J, Zimmerman T, et al. Consumption of low-calorie sweetened beverages is associated with higher total energy and sugar intake among children, NHANES 2011-2016. Pediatr Obes. 2019;2:e12535.
21. Fowler SPG. Low-calorie sweetener use and energy balance: results from experimental studies in animals, and large-scale prospective studies in humans. Physiol Behav. 2016;164(Pt B):517-523.
22. Azad MB, Abou-Setta AM, Chauhan BF, et al. Nonnutritive sweeteners and cardiometabolic health: a systematic review and meta-analysis of randomized controlled trials and prospective cohort studies. CMAJ. 2017;189: E929-E939.
23. Ruanpeng D, Thongprayoon C, Cheungpasitporn W, et al. Sugar and artificially-sweetened beverages linked to obesity: a systematic review and meta-analysis. QJM. 2017;110:513-520.
24. Blundell JE, Rogers PJ, Hill AJ. Uncoupling sweetness and calories: methodological aspects of laboratory studies on appetite control. Appetite. 1988;11(Suppl 1):54-61.
25. Bellisle F. Intense sweeteners, appetite for the sweet taste, and relationship to weight management. Curr Obes Rep. 2015;4:106-110.
26. Bryant CE, Wasse LK, Astbury N, et al. Non-nutritive sweeteners: no class effect on the glycaemic or appetite responses to ingested glucose. Eur J Clin Nutr. 2014;68:629-631.
27. Canty DJ, Chan MM. Effects of consumption of caloric vs noncaloric sweet drinks on indices of hunger and food consumption in normal adults. Am J Clin Nutr. 1991;53:1159-1164.
28. Meyer-Gerspach AC, Wolnerhanssen B, Beglinger C. Functional roles of low calorie sweeteners on gut function. Physiol Behav. 2016;164(Pt B):479-481.
29. Mattes RD, Popkin BM. Nonnutritive sweetener consumption in humans: effects on appetite and food intake and their putative mechanisms. Am J Clin Nutr. 2009;89:1-14.
30. Bhupathiraju SN, Pan A, Malik VS, et al. Caffeinated and caffeine-free beverages and risk of type 2 diabetes. Am J Clin Nutr. 2013;97:155-166.
31. Schulze MB, Manson JE, Ludwig DS, et al. Sugar-sweetened beverages, weight gain, and incidence of type 2 diabetes in young and middle-aged women. JAMA. 2004;292:927-934.
32. de Koning L, Malik VS, Rimm EB, et al. Sugar-sweetened and artificially sweetened beverage consumption and the risk of type 2 diabetes in men. Am J Clin Nutr. 2011;93:1321-1327.
33. Tey SL, Salleh NB, Henry CJ, et al. Effect of non-nutritive (artificial vs natural) sweeteners on 24-hour glucose profile. Eur J Clin Nutr. 2017;71:1129-1132.
34. Bonnet F, Tavenard A, Esvan M, et al. Consumption of a carbonated beverage with high-intensity sweeteners has no effect on insulin sensitivity and secretion in nondiabetic adults. J Nutr. 2018;148:1293-1299.
35. Higgins KA, Considine RV, Mattes RD. Aspartame consumption for 12 weeks does not affect glycemia, appetite, or body weight of healthy, lean adults in a randomized controlled trial. J Nutr. 2018;148:650-657.
36. Romo-Romo A, Aguilar-Salinas CA, Brito-Cordova GX, et al. Effects of the non-nutritive sweeteners on glucose metabolism and appetite regulating hormones: systematic review of observational prospective studies and clinical trials. PloS One. 2016;11:e0161264.
37. Greenwood DC, Threspleton DE, Evans CE, et al. Association between sugar-sweetened and artificially sweetened soft drinks and type 2 diabetes: systematic review and dose-response meta-analysis of prospective studies. Br J Nutr. 2014;112:725-734.
38. Imamura F, O’Conner L, Ye M, et al. Consumption of sugar sweetened beverages, artificially sweetened beverages, and fruit juice and incidence of type 2 diabetes: systematic review, meta-analysis, and estimation of population attributable fraction. BMJ. 2015;351:h3576.
39. Davis JN, Asigbee FM, Markowitz AK, et al. Consumption of artificial sweetened beverages associated with adiposity and increasing HbA1c in Hispanic youth. Clin Obes. 2018;8:236-243.
40. Gardner C, Wylie-Rosett J, Gidding SS, et al. Nonnutritive sweeteners: current use and health perspectives. a scientific statement from the American Heart Association and the American Diabetes Association. Diabetes Care. 2012;35:1798-1808.
41. American Diabetes Association. Standards of Medical Care in Diabetes—2019. Diabetes Care. 2019;42(Suppl 1):S1-S183.
42. Dietary Guidelines Advisory Committee. Scientific Report of the 2015 Dietary Guidelines Advisory Committee: advisory report to the Secretary of Health and Human Services and the Secretary of Agriculture. Office of Disease Prevention and Health Promotion Web site. https://health.gov/dietaryguidelines/2015-scientific-report/.Published February 2015. Accessed July 15, 2019.
43. Aune D. Soft drinks, aspartame, and the risk of cancer and cardiovascular disease. Am J Clin Nutr. 2012;96:1249-1251.
44. Artificial sweeteners and cancer. National Cancer Institute Web site. https://www.cancer.gov/about-cancer/causes-prevention/risk/diet/artificial-sweeteners-fact-sheet. Reviewed August 10, 2016. Accessed July 15, 2019.
45. Fung TT, Malik V, Rexrode KM, et al. Sweetened beverage consumption and risk of coronary heart disease in women. Am J Clin Nutr. 2009;89:1037-1042.
46. Lin J, Curhan GC. Associations of sugar and artificially sweetened soda with albuminuria and kidney function decline in women. Clin J Am Soc Nephrol. 2011;6:160-166.
47. Malik VS, Li Y, Pan A, et al. Long-term consumption of sugar-sweetened and artificially sweetened beverages and risk of mortality in US adults. Circulation. 2019;139:2113-2125.
48. Gardener H, Rundek T, Markert M, et al. Diet soft drink consumption is associated with an increased risk of vascular events in the Northern Manhattan Study. J Gen Inten Med. 2012;27:1120-1126.
49. Fitch C, Keim KS. Position of the Academy of Nutrition and Dietetics: use of nutritive and nonnutritive sweeteners. J Acad Nutr Diet. 2012;112:739-758.
50. US Food and Drug Administration. Additional information about high-intensity sweeteners permitted for use in food in the United States. https://www.fda.gov/food/ingredientspackaginglabeling/foodadditivesingredients/ucm397725.htm#Aspartame. Accessed May 26, 2019.
51. Sylvetsky AC, Gardner AL, Bauman V, et al. Nonnutritive sweeteners in breast milk. J Toxicol Environ Health. 2015;78:1029-1032.
52. Rajani C, Jia W. Disruptions in gut microbial-host co-metabolism and the development of metabolic disorders. Clin Sci (Lond). 2018;132:791-811.
53. Kho ZY, Lal SK. The human gut microbiome—a potential controller of wellness and disease. Front Microbiol. 2018;9:1835.
54. Nettleton JE, Reimer RA, Shearer J. Reshaping the gut microbiota: impact of low calorie sweeteners and the link to insulin resistance. Physiol Behav. 2016;164(Pt B):488-493.
55. Turnbaugh PJ, Hamady M, Yatsunenko T, et al. A core gut microbiome in obese and lean twins. Nature. 2009;457:480-484.
56. Cotillard A, Kennedy SP, Kong LC, et al. Dietary intervention impact on gut microbial gene richness. Nature. 2013;500:585-588.
57. Le Chatelier E, Nielsen T, Qin J, et al. Richness of human gut microbiome correlates with metabolic markers. Nature. 2013;500:541-546.
58. Abou-Donia MB, El-Masry EM, Abdel-Rahman AA, et al. Splenda alters gut microflora and increases intestinal p-glycoprotein and cytochrome P-450 in male rats. J Toxicol Environ Health A. 2008;71:1415-1429.
59. Anderson RL. Effect of saccharin ingestion on stool composition in relation to caecal enlargement and increased stool hydration. Food Chem Toxicol. 1983;21:255-257.
60. Suez J, Korem T, Zeevi D, et al. Artificial sweeteners induce glucose intolerance by altering the gut microbiota. Nature. 2014;514:181-186.
1. Adult obesity facts. Centers for Disease Control and Prevention Web site. https://www.cdc.gov/obesity/data/adult.html. Reviewed August 13, 2018. Accessed July 15, 2019.
2. Dietary guidelines for Americans 2015-2020: answers to your questions. USDA ChooseMyPlate.gov Web site. https://www.choosemyplate.gov/2015-2020-dietary-guidelines-answers-your-questions. Accessed July 15, 2019.
3. Additional information about high-intensity sweeteners permitted for use in food in the United States. US Food and Drug Administration Web site. https://www.fda.gov/food/food-additives-petitions/additional-information-about-high-intensity-sweeteners-permitted-use-food-united-states. Published February 8, 2018. Accessed July 15, 2019.
4. Magnuson B, for the Aspartame Expert Work Group. Nutritive and non-nutritive sweeteners. NNNS: aspartame, methanol and formaldehyde relationships (2011). https://www.foodsweeteners.com/wp-content/uploads/2015/08/Aspartame-Methanol-and-Formaldehyde-Relationships.pdf. Accessed July 15, 2019.
5. Jo JH, Kim S, Jeon TW, et al. Investigation of the regulatory effects of saccharin on cytochrome P450s in male ICR mice. Toxicol Res. 2017;33:25-30.
6. Shwide-Slavin C, Swift C, Ross T. Nonnutritive sweetener: where are we today? Diabetes Spectrum. 2012;25:104-110.
7. Chattopadhyay S, Raychaudhuri U, Chakraborty R. Artificial sweeteners – a review. J Food Sci Technol. 2014;51:611-621.
8. EFSA Panel on Food Additives and Nutrient Sources added to Food. Scientific opinion on the safety of advantame for the proposed uses as a food additive. EFSA Journal. 2013;11:3301.
9. Fitch C, Keim KS; Academy of Nutrition and Dietetics. Position of the Academy of Nutrition and Dietetics: use of nutritive and nonnutritive sweeteners. J Acad Nutr Diet. 2012;112:739-758.
10. Ng SW, Slining MM, Popkin BM. Use of caloric and non-caloric sweeteners in US consumer packaged foods, 2005-2009. J Acad Nutr Diet. 2012;112:1828-1834.
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PRACTICE RECOMMENDATIONS
› Advise patients who are trying to lose weight that non-nutritive sweeteners (NNSs) are not beneficial for weight loss. A
› Reassure patients that NNSs do not appear to cause, or increase the risk of, developing type 2 diabetes mellitus. A
Strength of recommendation (SOR)
A Good-quality patient-oriented evidence
B Inconsistent or limited-quality patient-oriented evidence
C Consensus, usual practice, opinion, disease-oriented evidence, case series
