Dear Sir:
The findings from the recent study by Tasevska et al (1) suggest that there is a difference in response to sugars between women and men. Similar to other cohort studies that found a sex difference for soda intake and stroke risk (2), Tasevska et al reported a significant positive cardiovascular mortality trend with greater intakes of sugar from beverages in women but not in men (1). Although the difference in sex physiology is a plausible explanation for these associations, the consideration for other differences in sex responses is necessary in the interpretation of these analyses.
The authors adjusted for total energy intake in their models. Taking this approach reduces the effect of potential confounding but does not address the underlying limitation of energy intake measurements: underreporting, which may lead to overestimation of the association between exposure and outcome. Although the Diet History Questionnaire used in the study has been validated and shown to have moderate correlations with 24-h recalls for added sugar assessment (0.68 in men and 0.79 in women) (3), the OPEN (Observing Protein and Energy Nutrition) Biomarker Study reported that the Diet History Questionnaire is still significantly limited by underreporting of energy intake (4). The underreporting of energy intake is concerning because a recent assessment of the validity of self-report dietary intake from 24-h recalls found that more than two-thirds of women have energy estimates that are not physiologically plausible (5). Furthermore, women also tend to underreport their energy intake much more than men (by ∼365 kcal/d in women and ∼281 kcal/d in men) (5). This inability to provide accurate estimations of energy intake limits our ability to interpret data and may have a significant impact on clinical decisions. Therefore, even when energy intake is adjusted in association models, these association models may not necessarily be free from the confounding effect of energy.
Other lines of high-quality evidence from systematic reviews and meta-analyses of controlled trials have shown excess energy to be an important mediating factor in the effects of fructose on cardiometabolic risk. In a series of Canadian Institutes of Health Research–funded (clinicaltrials.gov identifier NCT01363791) systematic reviews and meta-analyses of controlled feeding trials, we found that fructose in isocaloric exchange for other carbohydrates (energy-matched conditions between the fructose and carbohydrate comparator arms) showed no signal for harm in relation to body weight (6), fasting and postprandial lipids (7), glycemic control (8), insulin (8), blood pressure (9), and uric acid (9) and markers of nonalcoholic fatty liver disease (10). Although there may be a dose threshold for fasting lipids in some subgroup analyses (7), an overall lack of harm is seen even under conditions of fructose overfeeding (positive energy balance) at high doses, as long as the comparison with the carbohydrate comparator remains matched for the excess calories. A consistent signal for harm is only seen in imbalanced, hypercaloric comparisons, in which fructose supplements control diets with excess calories compared with the same control diets alone without the excess calories. In the absence of a clear effect on cardiometabolic risk factors in isocaloric comparisons (especially under conditions of positive energy balance), fructose does not appear to be any worse than other refined carbohydrates. The implication is that the adverse effects seen in the hypercaloric comparisons relate to the excess energy rather than the fructose. Consideration for total energy intake would therefore seem to be essential in understanding whether an association with fructose exists beyond the energy it contributes.
In conclusion, underreporting of energy complicates the interpretation of the association between sugar intake and cardiovascular mortality risk. This issue is especially important when considering the response observed in women because they are more likely to underreport their energy intake than men. To address the issue of energy as a confounding factor, isocaloric randomized controlled trials are needed to isolate the true effect of sugar intake, independent of energy intake, on cardiovascular health.
Acknowledgments
RJdS is supported by a Canadian Institutes of Health Research (CIHR) Postdoctoral Fellowship Award.
VH has received research support from the Canadian Institutes of Health Research (CIHR) and the WHO for work on a systematic review and meta-analysis commissioned by WHO of the relation of SFAs with health outcomes. She received a travel award to attend a science day hosted by PepsiCo and the New York Academy of Sciences. LC has received research support from CIHR and the Agricultural Bioproducts Innovation Program through the Pulse Research Network (PURENet) and Saskatchewan Pulse Growers. She is also a casual clinical research coordinator at Glycemic Index Laboratories. RJdS has received research support from the CIHR, the Calorie Control Council, the Canadian Foundation for Dietetic Research, and the Coca-Cola Company (investigator-initiated, unrestricted grant). He has served as an external resource person to WHO’s Nutrition Guidelines Advisory Group and received travel support from WHO to attend group meetings. He is the lead author of 2 systematic reviews and meta-analyses commissioned by WHO of the relation of SFAs and trans fatty acids with health outcomes. CWCK has received research support from the Advanced Foods and Material Network, Agrifoods and Agriculture Canada, the Almond Board of California, the American Pistachio Growers, Barilla, the California Strawberry Commission, the Calorie Control Council, CIHR, the Canola Council of Canada, the Coca-Cola Company (investigator-initiated, unrestricted grant), Hain Celestial, the International Tree Nut Council Nutrition Research and Education Foundation, Kellogg, Kraft, Loblaw Companies Ltd, Orafti, Pulse Canada, Saskatchewan Pulse Growers, Solae, and Unilever. He has received travel funding, consultant fees, or honoraria from Abbott Laboratories, the Almond Board of California, the American Peanut Council, the American Pistachio Growers, Barilla, Bayer, the Canola Council of Canada, the Coca-Cola Company, Danone, General Mills, the International Tree Nut Council Nutrition Research and Education Foundation, Kellogg, Loblaw Companies Ltd, the Nutrition Foundation of Italy, Oldways Preservation Trust, Orafti, Paramount Farms, the Peanut Institute, PepsiCo, Pulse Canada, Sabra Dipping Co, Saskatchewan Pulse Growers, Solae, Sun-Maid, Tate and Lyle, and Unilever. He is on the Dietary Guidelines Committee for the Diabetes Nutrition Study Group of the European Association for the Study of Diabetes (EASD) and has served on the scientific advisory boards for the Almond Board of California, the International Tree Nut Council, Oldways Preservation Trust, Paramount Farms, and Pulse Canada. JLS has received research support from CIHR, the Calorie Control Council, the Coca-Cola Company (investigator-initiated, unrestricted), Dr Pepper Snapple Group (investigator-initiated, unrestricted), Pulse Canada, and the International Tree Nut Council Nutrition Research and Education Foundation. He has received travel funding, speaker fees, and/or honoraria from the American Heart Association, the American College of Physicians, the ASN, the National Institute of Diabetes and Digestive and Kidney Diseases of the NIH, the Canadian Diabetes Association, the Canadian Nutrition Society, the University of South Carolina, the University of Alabama at Birmingham, Oldways Preservation Trust, the Nutrition Foundation of Italy, Calorie Control Council, the Diabetes and Nutrition Study Group of the EASD, International Life Sciences Institute (ILSI) North America, ILSI Brazil, Abbott Laboratories, Pulse Canada, the Canadian Sugar Institute, Dr Pepper Snapple Group, the Coca-Cola Company, the Corn Refiners Association, and the World Sugar Research Association. He has consulting arrangements with Tate & Lyle, Perkins Coie LLP, and Winston & Strawn LLP. He is on the Clinical Practice Guidelines Expert Committee for Nutrition Therapy of both the Canadian Diabetes Association and EASD, as well as being on an ASN writing panel for a scientific statement on the metabolic and nutritional effects of fructose, sucrose, and high-fructose corn syrup. He is a member of the International Carbohydrate Quality Consortium and a board member of the Diabetes and Nutrition Study Group of the EASD. He serves as an unpaid scientific advisor for the ILSI North America, Food, Nutrition, and Safety Program (FNSP). His wife is an employee of Unilever Canada.
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