Added Sugars and Risk Factors for Obesity, Diabetes and Heart Disease

REVIEW Added sugars and risk factors for obesity, diabetes and heart disease

JM Rippe1,2,3 and TJ Angelopoulos4

The effects of added sugars on various chronic conditions are highly controversial. Some investigators have argued that added sugars increase the risk of obesity, diabetes and cardiovascular disease. However, few randomized controlled trials are available to support these assertions. The literature is further complicated by animal studies, as well as studies which compare pure fructose to pure glucose (neither of which is consumed to any appreciable degree in the human diet) and studies where large doses of added sugars beyond normal levels of human consumption have been administered. Various scientiﬁc and public health organizations have offered disparate recommendations for upper limits of added sugar. In this article, we will review recent randomized controlled trials and prospective cohort studies. We conclude that the normal added sugars in the human diet (for example, sucrose, high-fructose corn syrup and isoglucose) when consumed within the normal range of normal human consumption or substituted isoenergetically for other carbohydrates, do not appear to cause a unique risk of obesity, diabetes or cardiovascular disease.

International Journal of Obesity (2016) 40, S22–S27; doi:10.1038/ijo.2016.10

INTRODUCTION added sugars with a particular emphasis on sucrose and HFCS, Few topics in nutrition are as controversial as added sugars.1–17 It which are the most common sources of added sugars in the has been argued that added sugars may be associated with human diet. increased risk of obesity,4,8 diabetes18,19 and cardiovascular The purpose of the current review is to present data from recent disease (CVD),20,21 and a variety of other adverse health randomized controlled trials (RCTs) and other high-level evidence consequences. These assertions are largely based on epidemio- such as systematic reviews and meta analyses of prospective logic studies or animal data. The issue is further clouded by cohorts, on added sugars and their potential effect on obesity, published literature comparing the effects of pure fructose to pure diabetes and CVD. Although it has been argued that these three glucose, despite the fact that neither is consumed to any metabolically based conditions are so closely allied that we ought appreciable degree in the human diet.22–25 The major sources of to consider them all as one entity that some investigators have ‘ ’ added sugars in the human diet are sucrose (50% fructose and called cardiodiaobesity , for the purposes of this review, we will 50% glucose), high-fructose corn syrup (HFCS; either HFCS-55, separate the three into separate entities. We also intend to offer which is 55% fructose and 45% glucose or glucose polymers; or comments on our view for the appropriate upper limit of added HFCS-42, which is 42% fructose and 58% glucose or glucose sugars in the human diet. polymers).13,14 HFCS is also called isoglucose in Europe. Thus, the major sources of added sugars in the human diet contain roughly 50% fructose and 50% glucose, which is also the way that they are SUGAR METABOLISM found in nature in many fruits, vegetables and nuts. Many of the theoretical arguments concerning fructose- Concern over the potential adverse consequences of added containing sugars are based on the well-known differences in sugar has caused the American Heart Association,26 the Scientific metabolism between fructose and glucose.32 Fructose metabolism Advisory Committee on Nutrition in England,27 the World Health differs from glucose in two major ways: Organization28 and the Dietary Guidelines Advisory Committee 2015 (ref. 21) to recommend restricting added energy from sugar ● Nearly complete hepatic extraction of fructose. to no more than 10% of energy intake. In contrast, the Institute of ● Different enzymatic reactions in the initial steps of fructose Medicine Carbohydrate report,29 on which the 2010 Dietary versus glucose metabolism. Guidelines for Americans30 was based, suggests an upper limit of no more than 25% of energy intake. Although the pathways of metabolism are different in the liver, Sugars may be classified as ‘naturally occurring’ or ‘added’. it must be emphasized that they are interactive. Indeed, multiple Added sugars are defined as sugars or syrups added to foods studies have shown that approximately 50% of fructose metabo- during processing or preparation including those sugars and lized by the liver is converted into glucose in hepatic cells, syrups added at the table.31 In this review, we will focus largely on approximately 15–18% of the glucose is converted into glycogen

1Rippe Lifestyle Institute, Shrewsbury, MA, USA; 2Rippe Lifestyle Research Institute of Florida, Celebration, FL, USA; 3University of Central Florida, Orlando, FL, USA and 4School of Health Sciences, Emory and Henry College, Emory, VA, USA. Correspondence: Dr JM Rippe, Rippe Lifestyle Institute, 21 North Quinsigamond Avenue, Shrewsbury, MA 01545, USA. E-mail: [email protected] This article is based on a presentation at a symposium entitled ‘Sweeteners and Health: Findings from Recent Research and their Impact on Obesity and Related Metabolic Conditions’ held at the European Congress on Obesity (ECO) on 7 May 2015. This symposium was supported, in part, by an educational grant from Rippe Lifestyle Institute. Added sugars and risk factors for chronic disease JM Rippe and TJ Angelopoulos S23 and 25% to lactate, while several percent is immediately oxidized whereas obesity rates have continued to rise, or remain stable, in 32,33 to CO2. A small portion of either fructose or glucose may be most population groups. These data are consistent with those converted in the process of de novo lipogenesis into fatty acids reported by Welsh et al.36 based on an analysis of NHANES data, that may be stored as triglycerides in hepatocytes or released in which estimated a 15% decrease in added sugar consumption in the systemic circulation in the very low-density lipoprotein the United States from 2000 to 2012. particle. In human beings, de novo lipogenesis is a minor pathway consisting of no more than 1–5% of fructose converted into fatty acids or triglycerides.32–34 ADDED SUGARS, OBESITY AND BODY COMPOSITION Moreover, as fructose and glucose are rarely, if ever, consumed Initial interest in the United States in a potential linkage between in isolation in the human diet, the consumption of fructose and sugar consumption and obesity can be traced back as early as glucose together may further alter the metabolism of both these 1950 with the publication of a book by John Yudkin entitled ‘Pure, sugars. It has also been argued that minor differences in HFCS and White and Deadly’.37 Interest in this topic, however, was minimal sucrose may alter metabolism. In particular, it has been argued compared with the role of fats in the diet through the publication that the covalent bond between glucose and fructose in sucrose is of Ancel Keys’ classic Seven Countries Study.38 different as compared with the fructose and glucose found The issue of a potential role for sugars in obesity resurfaced in separately in HFCS. As a practical matter, however, the enzyme 2004, when George Bray and Barry Popkin argued that increasing sucrase, in the small intestine, immediately cleaves virtually all the use of HFCS in the United States was temporally associated with a 4 bonds between glucose and fructose in sucrose. Thus, both HFCS rapid increase in obesity prevalence. These authors based their and sucrose enter the blood stream as pure fructose and pure argument on the differences in metabolism of fructose compared glucose.21 Numerous studies have shown that there are no with glucose, which they argued could lead to over-consumption physiologic or metabolic differences between HFCS and sucrose.17 of energy. Subsequent research trials, however, have failed to Furthermore, it should also be pointed out that many of the support the hypothesized unique linkage between HFCS and covalent bonds between fructose and glucose in sucrose are likely obesity and have demonstrated that HFCS and sucrose are virtually identical with regard to energy, sweetness and to have been broken before even ingesting sucrose-containing 39–43 products through the process of inversion.14 In fact, in a 3-month absorption. As a result of this expanding research literature, study, all the sucrose consumed was ultimately found to be emphasis has shifted to a consideration whether or not fructose- inverted into its components of fructose and glucose before containing sugars, in general (for example, sucrose, HFCS and consumption. concentrated fruit juices and so on), might be causally linked to obesity. There have been three recent systematic reviews and meta SUGAR CONSUMPTION analyses of RCTs of sugar consumption or sugar-sweetened 44–46 Many misconceptions about the consumption of added sugars beverage consumption and body weight. These meta analyses of RCTs demonstrate that when sugar is replaced with have resulted in the focus on reducing these nutrients as a energy-equivalent macronutrients, no increase in body weight strategy for lowering the risk of obesity and other public health occurs. These meta analyses provided some evidence to suggest concerns. Perhaps the most prevalent misconception is that sugar that if energy consumption is increased by adding sugar to an consumption has risen dramatically over the past 4 years.14 already isoenergetic diet in adults, this may lead to modest weight Figure 1 compares the trends in consumption of sugar, HFCS, gain. The weight gain, however, appeared to be a function of fructose and added sugars. This figure is derived from USDA-ERS 35 increased energy consumption rather than sugars per se. per capita availability data that are adjusted for loss. It provides a Prospective cohort trials have yielded similar results. reasonable estimate for consumption figures based on production fi The problem with many published studies results from failure to gures after corrections for amounts wasted (uneaten), which adjust for total energy intake. Once this adjustment has been occur between manufacturing and ingestion. made, results have typically shown no relation between sugar fi A number of points are apparent from studying this gure. First, consumption and body weight. Several recent summary articles from 1970 to 1989, the amount of HFCS in the American diet have reached the same result concluding that there is a lack of increased substantially. However, the amount of sucrose con- high quality evidence linking sugars uniquely to obesity.3,44,47 sumed declined in an almost mirror image manner. Thus, the total RCTs performed in our research laboratory have shown that amount of sugars consumed remained relatively constant. consumption of average amounts of fructose-containing sugars Furthermore, total sugar intake in the United States peaked in do not yield increased body weight in either a 10-week free-living 1999 and has been in a substantial decline since that time, study39 or a 24-week study (unpublished data). Thus, a variety of sources of high quality evidence do not support the contention 120.0 that sugars per se make a unique contribution to obesity. Further evidence counter to a unique role for sugars stimulating 100.0 obesity comes from the observation that obesity rates have continued to rise not only in the United States48 and Great 80.0 Britain,49 but also in Australia,50 while sugar-sweetened beverage consumption has declined. This has become known as the 60.0 ‘Australian Paradox’ and adds further suggestive evidence that there is no unique relationship between sugars and obesity. 40.0 availability, Finally, it should be emphasized that in a condition as complicated as obesity, it is highly unlikely that a single nutrient

Sweetener per capita 20.0 would uniquely cause this condition. This view is consistent with a

loss adjusted (grams per day) recent scientiﬁc statement from the American Society of Nutrition, 0.0 which cautioned against isolating one component of the diet as a 1970 1973 1976 1979 1982 1985 1988 1991 1994 1997 2000 2003 2006 2009 2012 primary driver of weight gain and obesity and emphasized the Sugar HFCS Added sugars Fructose complexity of energy regulation.51 Americans and individuals in Figure 1. Comparison of trends in per capita availability (loss many other countries around the world are becoming more obese adjusted) of nutritive sweeteners.35 largely because they are eating more of everything, not just

© 2016 Macmillan Publishers Limited International Journal of Obesity (2016) S22 – S27 Added sugars and risk factors for chronic disease JM Rippe and TJ Angelopoulos S24 sugars. In fact, in the United States, it has been reported that the CVD.61–74 For this reason, the American Heart Association average energy intake increased by 454 kcal per day between Scientific Statement on triglycerides lists avoiding fructose as 1970 and 2010, while only 39 of these kcal came from all added one mechanism for preventing hypertriglyceridemia.75 Elevated sugars combined (9% of the increase).35 triglycerides may result from increased hepatic triglyceride synthesis as well as reduced peripheral clearance of triglycerides, both of which have been attributed to increased fructose SUGAR AND DIABETES metabolism. In our research laboratory, an isoenergetic trial Diabetes has emerged as a major and rapidly growing worldwide involving 65 individuals, where no weight gain occurred, did not health concern in the twenty-first century. The prevalence of result in increased triglycerides.76 However, a much larger study diabetes is predicted by the International Diabetes Federation to involving 355 men and women between the ages of 20–60 years, double by 2035.52 This dramatic increase in diabetes has who were randomly assigned to consume either 8, 18 or 30% of paralleled the worldwide increase in obesity and has prompted total energy as sucrose or HFCS resulted in a 10% increase in further investigation of potential nutritional links to diabetes. One triglycerides.57 However, in this latter trial, individuals consumed of the factors that has been suggested as a unique link to diabetes an average of over 200 kcals per day more by the end of the study, is the consumption of fructose-containing sugars. compared with baseline, and gained an average of over two Several recent ecological studies have suggested that as sugar pounds (1 kg). Thus, it is not clear that the increased triglycerides consumption has increased in countries so has the prevalence of were a function of weight gain and increased energy intake or diabetes.18,19 However, these analyses are considered a very weak sugars per se. Several recent systematic reviews and meta analyses form of scientific evidence and have been criticized on multiple have reported that hypercaloric feeding of fructose results in levels, particularly for utilizing production data and confusing it increased triglycerides, but studies where fructose is substituted with consumption data.47 Furthermore, other ecologic studies isoenergetically for other carbohydrate sources have not resulted from the United States, England and Australia have all suggested in increased triglycerides.77,78 that obesity rates continue to rise, despite decreasing sugar Diets high in simple sugars have been reported to also result in consumption.48–50 decreased HDL cholesterol.79,80 However, diets that are high in The central question about whether sugar is the unique cause complex carbohydrates, such as the DASH diet, which substitute of diabetes has not been specifically addressed in any RCT. Thus, fat with complex carbohydrates and low-fat dairy products, fruits most of the data related to this issue come from studies looking at and vegetables and whole grains have not been reported to risk factors for diabetes rather than diabetes per se. increase triglycerides, although they may result in a modest Prospective cohort studies provide mixed evidence concerning decrease in HDL cholesterol. sugar consumption and diabetes.53,54 Some studies have sug- The effects of sugar on total cholesterol and LDL cholesterol gested an effect of sugar-sweetened beverages on the incidence have been variable. Some investigators have found increases in of diabetes.53,54 However, many did not adjust findings for energy LDL cholesterol,65,69,70,74 while others have not demonstrated such intake and body weight. Other prospective cohort studies have increases.81 Many of the studies that have shown increases in LDL not found a significant association between sugar intake and have given either large doses of sugars well above the physiologic diabetes.55,56 normal range69,70 or have given very large doses of either pure Several recent RCTs conducted in our laboratory have not fructose or pure glucose.82 Trials in our laboratory at levels of demonstrated an increase in risk factors for diabetes in response sugar consumption between the 25th and 95th population to multiple levels of added sugar consumption between 8% and consumption level have not demonstrated changes in LDL 30% of energy.57–59 In one study where individuals consumed following 10 weeks of a free-living environment compared with 18% of total energy from either sucrose or HFCS or 9% of energy baseline.57 from fructose and glucose, no increase in fasting glucose, insulin Thus, it would appear that there is a marker for increased or insulin resistance via the homeostatic model assessment triglycerides when levels of 420% of total energy are consumed occurred.59 In another study with 267 individuals who consumed as sugars, particularly in hypercaloric settings. However, the effects either 8%, 18% or 30% of total energy from added sugars, no of fructose-containing sugars on LDL cholesterol remain in increases in glucose, insulin or insulin resistance were found.57 dispute, particularly in isoenergetic trials. Furthermore, a previous study in our research laboratory involving 68 individuals consuming either HFCS or sucrose at up to 30% of Blood pressure total energy did not show any increase in ectopic fat in muscle or 83 Johnson et al. have proposed a model where increased liver, both of which have been implicated in increased insulin consumption of fructose may be linked to increases in blood resistance.60 pressure. According to this model, rapid metabolism of fructose in Just as with obesity, the etiology of type 2 diabetes is certainly the liver may deplete adenosine triphosphate, which is degraded complicated and not entirely resolved. However, the most likely into adenosine monophosphate and ultimately metabolized to primary pathologic event is excess energy intake leading to uric acid. Uric acid, in turn, in this model is thought to lead to overweight and obesity. Taken together, the current available endothelial dysfunction, which increases the risk of high blood evidence does not suggest that sugar consumption per se pressure. uniquely increases the risk of diabetes. Clinical trials, however, on blood pressure and sugar consumption have reported variable results.84–87 Studies from our research SUGARS AND CARDIOVASCULAR DISEASE laboratory and others have shown neither increases in blood pressure, nor uric acid levels resulting from 10 weeks of sugar There have been no RCTs to explore the relationship between consumption at up to 30% of total energy, which represents the sugars and cardiovascular disease per se. Thus, most of these 95% percentile population consumption level of fructose.17 scientific studies have focused on the relationship between sugars Systematic reviews and meta analyses have also reported and risk factors for CVD. conflicting results with regard to added sugar and blood pressure. Ha et al.85 reported a systematic review and meta analysis of 18 Lipids studies (n = 355) and showed slight decreases in both diastolic and Diets that are high in simple sugars (420% of total energy) may mean blood pressure when fructose was substituted either result in elevated fasting triglycerides, an established risk factor for isoenergetically (13 trials) for other carbohydrates or in

International Journal of Obesity (2016) S22 – S27 © 2016 Macmillan Publishers Limited Added sugars and risk factors for chronic disease JM Rippe and TJ Angelopoulos S25 hypercaloric trials (two trials). Te Morenga et al.20 reported 12 trials Citrus, PepsiCo International, The Coca Cola Company, Dr. Pepper/Snapple Group, (n = 324) with no significant effects of higher sugar intake on Corn Refiners Association, Weight Watchers International as well as royalties and systolic blood pressure overall (mean difference: 1.1 mm Hg; editorial office support from CRC Press, Sage Publishing and Springer Publishers. The P = 0.32). Higher sugar intake was, however, associated with remaining author (TJA) declares no conflict of interest. greater diastolic blood pressure of 1.1 mm Hg (P = 0.02). Many of the trials reported in this systematic review, however, used levels ACKNOWLEDGEMENTS of added sugar consumption above the 90th percentile popula- ‘ tion consumption level. This article is based on a symposium entitled Sweeteners and Health: Findings from ’ Thus, the effects of simple sugars on blood pressure at normal Recent Research and their Impact on Obesity and Related Metabolic Conditions presented at the 22nd European Congress on Obesity, Prague, on 7 May 2015 with population levels remain in dispute, with most of the high quality sponsorship from Rippe Lifestyle Institute. evidence from trials within the normal range of human consumption reporting no unique linkage. REFERENCES WHAT ARE THE APPROPRIATE UPPER LIMITS OF ADDED 1 Rippe JM, Angelopoulos TJ. Sucrose, high-fructose corn syrup, and fructose, their SUGAR CONSUMPTION? metabolism and potential health effects: what do we really know? Adv Nutr 2013; 4:236–245. As already indicated, numerous scientific bodies have offered 2 Rippe J. The metabolic and endocrine response and health implications of con- recommendations for upper limits of sugar consumption. 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