We thank Buziau et al. (1) for their letter. Using Mendelian randomization, the authors examined the association between the rs2304681 minor allele in the gene encoding ketohexokinase and cardiometabolic outcomes. rs2304681 is a missense variant that impairs fructose metabolism, thereby acting as a proxy for fructose exposure. This allows for the examination of the association of fructose with cardiometabolic outcomes, a proposed mechanism by which sugar-sweetened beverages (SSBs) contribute to excess cardiometabolic harm.
Several lines of evidence suggest that SSBs contribute to cardiometabolic harm, with guidelines recommending a reduction in consumption. However, the optimal clinical and public health strategies for achieving SSB reduction were hitherto unclear due to limited evidence on the role of replacement beverages (e.g., low- and no-calorie sweetened beverages [LNCSBs]). Our recent findings of a systematic review and meta-analysis of prospective cohort studies (2) and randomized controlled trials (3) demonstrated that LNCSBs can be used as a replacement strategy similar to that for water for reducing cardiometabolic harm from SSBs. These studies also provided evidence that the causal pathway between SSBs and cardiometabolic outcome is via excess energy. New methodologies, including Mendelian randomization, can be a powerful tool to examine diet–disease relationships. However, the causal pathway between the exposure to SSBs and cardiometabolic outcomes, which is driven by excess energy, cannot be reduced to a single nutrient due to the complexity of nutrient interaction, the food matrix in which the nutrients are contained, and other consumption behaviors. Our previous systematic review and meta-analysis of cohort studies showed that fructose intake was not associated with diabetes, hypertension, or cardiovascular disease incidence (4) and had a nonlinear U-shape with cardiovascular disease mortality, indicating that while excess intake can be harmful, moderate intake might be associated with protection. Such a relationship can be understood when looking at the consumption behaviors of fructose (i.e., as part of a food source rather than as a single ingredient). Traditional extreme quantile meta-analyses and dose-response meta-analyses of food sources of fructose showed that SSBs were associated with increased risk of diabetes, metabolic syndrome, and hypertension, while yogurt, fruit, 100% fruit juice, and whole-grain breakfast cereals showed protective associations. Similarly, systematic review and meta-analysis of randomized controlled trials failed to show a harmful effect of fructose in energy-matched substitutions with other carbohydrates on cardiometabolic outcomes, with a signal for harm seen only when fructose provided excess energy (5). When intervention studies were stratified further by food source, cardiometabolic harm was observed only when fructose was consumed as SSBs providing excess energy, while other food sources in energy-matched substitutions failed to show harm. These results align with those of Buziau et al. (1) by demonstrating the signal for cardiometabolic harm occurs when fructose provides excess energy in the form of SSBs; however, the results do not necessarily extend to fructose from other important food sources. Further investigation of the causal pathway between SSBs and cardiometabolic outcomes and the role of LNCSBs in that pathway are warranted to further understand this relationship.
See accompanying article, p. e97.
Funding and Duality of Interest. J.J.L. receives research support from the Canadian Institutes of Health Research (CIHR) and has received research support from the Banting and Best Diabetes Centre at the University of Toronto. T.A.K. has received research support from the CIHR, the International Life Science Institute (ILSI), and the National Honey Board. He has taken honorarium for lectures from the International Food Information Council and Institute for the Advancement of Food and Nutrition Sciences (IAFNS, formerly ILSI North America). J.L.S. has received research support from the Canadian Foundation for Innovation, Ontario Research Fund, Province of Ontario Ministry of Research and Innovation and Science, CIHR, Diabetes Canada, American Society for Nutrition, International Nut and Dried Fruit Council Foundation, National Honey Board (U.S. Department of Agriculture [USDA] honey “Checkoff” program), IAFNS, Pulse Canada, Quaker Oats Center of Excellence, the United Soybean Board (USDA soy “Checkoff” program), the Tate & Lyle Nutritional Research Fund at the University of Toronto, the Glycemic Control and Cardiovascular Disease in Type 2 Diabetes Fund at the University of Toronto (a fund established by the Alberta Pulse Growers), the Plant Protein Fund at the University of Toronto (a fund that has received contributions from International Flavors & Fragrances), and The Nutrition Trialists Network Fund at the University of Toronto (a fund established by an inaugural donation from the Calorie Control Council). He has received food donations to support randomized controlled trials from the Almond Board of California, California Walnut Commission, Peanut Institute, Barilla, Unilever/Upfield, Unico/Primo, Loblaw Companies, Quaker, Kellogg Canada, WhiteWave Foods/Danone, Nutrartis, and Dairy Farmers of Canada. He has received travel support, speaker fees, and/or honoraria from the American Society for Nutrition, Danone, Dairy Farmers of Canada, FoodMinds LLC, Nestlé, Abbott, General Mills, Nutrition Communications, International Food Information Council, Calorie Control Council, International Sweeteners Association, and International Glutamate Technical Committee. He has or has had ad hoc consulting arrangements with Perkins Coie LLP, Tate & Lyle, Phynova, and Inquis Clinical Research. He is a former member of the European Fruit Juice Association Scientific Expert Panel and former member of the Soy Nutrition Institute Scientific Advisory Committee. He is on the Clinical Practice Guidelines Expert Committees of Diabetes Canada, European Association for the Study of Diabetes, Canadian Cardiovascular Society, and Obesity Canada/Canadian Association of Bariatric Physicians and Surgeons. He serves or has served as an unpaid member of the Board of Trustees and an unpaid scientific advisor for the Carbohydrates Committee of IAFNS. He is a member of the International Carbohydrate Quality Consortium, executive board member of the Diabetes and Nutrition Study Group of the European Association for the Study of Diabetes, and director of the Toronto 3D Knowledge Synthesis and Clinical Trials foundation. His spouse is an employee of AB InBev. No other potential conflicts of interest relevant to this article were reported.