Rationale, Design, and Participant Baseline Characteristics of a Parallel Randomized Trial of the Effect of Replacing SSBs with Cow's Milk Versus Soymilk on Intrahepatocellular Lipid and Other Cardiometabolic Risk Factors in Adults with Obesity Who Consume Sugar-Sweetened Beverages: The Soy Treatment Evaluation for Metabolic health (STEM) Trial
- PMID: 41978078
- PMCID: PMC13074930
- DOI: 10.3390/nu18071026
Rationale, Design, and Participant Baseline Characteristics of a Parallel Randomized Trial of the Effect of Replacing SSBs with Cow's Milk Versus Soymilk on Intrahepatocellular Lipid and Other Cardiometabolic Risk Factors in Adults with Obesity Who Consume Sugar-Sweetened Beverages: The Soy Treatment Evaluation for Metabolic health (STEM) Trial
Abstract
Background/Objectives: Liver fat represents an early metabolic lesion in the development of diabetes and its cardiometabolic complications. Diets high in free sugars, particularly from sugar-sweetened beverages (SSBs), are associated with abdominal obesity and increased cardiometabolic risk, prompting global guidelines to limit SSBs as a major public health strategy. Low-fat cow's milk is promoted as the preferred caloric replacement strategy for SSBs due to its high nutritional value and cardiometabolic advantages. Fortified soymilk is a plant-based alternative with approved health claims for cholesterol and coronary heart disease risk reduction that offers an equivalent nutritional value to cow's milk. However, given concerns about its classification as an ultra-processed food (UPF), it is unclear whether soymilk offers comparable metabolic health benefits to milk as part of clinical and public health strategies to reduce SSB intake. The Soy Treatment Evaluation for Metabolic (STEM) health trial seeks to evaluate the impact of replacing SSBs with either 2% soymilk or 2% cow's milk on liver fat and other cardiometabolic risk factors in habitual adult consumers of SSBs with obesity. Methods: The STEM trial is a 24-week, pragmatic, 3-arm, parallel, randomized trial. We recruited adults with obesity (high BMI plus high waist circumference based on ethnic specific cut-offs) consuming ≥1 SSB/day. Participants were randomized to one of three groups based on their usual SSB intake at baseline (servings/day): continued SSB (355 mL can) intake; replacement with fortified, sweetened 2% soymilk (250 mL); or replacement with 2% cow's milk (250 mL). The primary outcome is the change in intrahepatocellular lipid (IHCL) measured by 1H-MRS at 24 weeks. Hierarchical testing will be done to reduce the familywise error rate. The superiority of cow's milk to SSBs will be assessed first to establish assay sensitivity. If superiority is established, then the non-inferiority of soymilk to cow's milk will be assessed using a pre-specified non-inferiority margin of 1.5% IHCL units (assessed by difference of means using a 90% confidence interval [CI]). Analyses will be conducted according to the intention-to-treat (ITT) principle using inverse probability weighting (IPW) for superiority testing and per-protocol analyses for non-inferiority testing, using ANCOVA adjusted for age, sex, metabolic dysfunction-associated steatotic liver disease (MASLD) status, medication use, intervention dose, and baseline levels. We hypothesize that soymilk will be non-inferior to cow's milk (Clinicaltrials.gov NCT05191160). Results: Recruitment began in November 2021. A total of 3050 individuals were screened. We randomized 186 participants (62 per group) between 19 April 2022 and 16 April 2024. Participants are 57% male; with a mean [SD] age of 39.9 [11.8] years; BMI of 34.6 [6.1] kg/m2, waist circumference of 112.6 [13.8] cm; IHCL of 10.0 [8.2] % with 64.1% meeting the criteria for MASLD; and SSBs intake of 2.3 [1.3] servings/day. Conclusions: Baseline characteristics were balanced across the study arms, with participants representing adults with a high-risk metabolic phenotype, and 64.1% meeting the criteria for MASLD. Findings will contribute to evidence on the cardiometabolic benefits of soymilk, informing clinical practice guidelines and public health policy.
Keywords: abdominal obesity; cow’s milk; dietary intervention; glucose control; insulin sensitivity; liver fat; metabolic impairment; obesity; overweight; randomized controlled trial; soymilk; sugar-sweetened beverages; type 2 diabetes.
Conflict of interest statement
M.N.E. has received funding from the United Soybean Board (the United States Department of Agriculture [USDA] Soy “Check-off” Program), the Toronto 3D PhD Scholarship, the CIHR Canadian Graduate Scholarship Master’s Award, and the CIHR Graduate Scholarship Doctoral Award. D.G. has received funding from the Ontario Graduate Scholarship and the Toronto 3D PhD Scholarship. S.A.-C. has received an honorarium from the International Food Information Council (IFIC) (for a talk on NNS and the microbiome) and from the Arkansas Children’s Hospital for participation in a “lumping vs. splitting” event. T.A.K. discloses receiving research grants from Diabetes Canada, the CIHR, the Institute for the Advancement of Food and Nutrition Sciences (IAFNS, formerly ILSI North America), the National Honey Board (USDA Checkoff Program), and the Toronto 3D Knowledge Synthesis and Clinical Trials Foundation. T.A.K. has received honoraria for speaking engagements or advisory roles from IAFNS, IFIC, the Calorie Control Council (CCC), the International Sweeteners Association (ISA), AmCham Dubai, and the Ontario Maple Syrup Producers’ Association (OMSPA). Additionally, T.A.K. has served as a consultant for Heartland Foods Product Group. H.C. has received funding from the Undergraduate Summer Research Opportunity Program (UROP) award and the Toronto 3D Summer Scholarship Top-up Award. A.B. has received funding from the Toronto 3D Summer Scholarship Award. CS has received funding from the CIHR Canadian Graduate Scholarship Master’s Award. D.D.R. has received research support from Pulse Canada, the Saskatchewan Pulse Growers Association, and the Ontario Bean Growers Association. A.H.M. has received research support from CIHR, CFI, NSERC, and was a co-applicant on a joint government/industry funder research grant with Natures Crops International. He is a Scientific Advisor for Natures Crops International and Benexia and is on the Board of Directors of the International Society for the Study of Fatty Acids and Lipids. R.P.B. has received industrial grants, including those matched by the Canadian government, and/or travel support or consulting fees largely related to work on brain fatty acid metabolism from Arctic Nutrition (Ørsta, Norway), Bunge Ltd. (St. Louis, MO, USA), DSM (Heerlen, The Netherlands), Fonterra Inc. (Auckland, New Zealand), Mead Johnson (Chicago, IL, USA), Natures Crops International (Raleigh, NC, USA), Nestec Inc. (Vevey, Switzerland), Pharmavite (West Hills, CA, USA), and Sancero Inc. (Fort Worth, TX, USA). RPB is on the executive of the International Society for the Study of Fatty Acids and Lipids and held a meeting on behalf of Fatty Acids and Cell Signaling, both of which rely on corporate sponsorship, and has given expert testimony in relation to supplements and the brain. C.W.C.K. has received grants or research support from the Advanced Food Materials Network, Agriculture and Agri-Foods Canada, Almond Board of California, American Pistachio Growers, Barilla (Parma, Italy), Calorie Control Council, Canadian Institutes of Health Research, Canola Council of Canada, International Nut and Dried Fruit Council, International Tree Nut Council Research and Education Foundation, Loblaw Brands, Pulse Canada, Saskatchewan Pulse Growers and Unilever; has received in-kind research support from the Almond Board of California, American Peanut Council, Barilla, California Walnut Commission, Kellogg Canada, Loblaw Companies (Brampton, ON, Canada), Quaker (PepsiCo) (New York, NY, USA), Primo (Toronto, ON, Canada), Unico (Concord, ON, USA), Unilever (London, UK), WhiteWave Foods (Denver, CO, USA); has received travel support or honorariums from the American Peanut Council, American Pistachio Growers, Barilla, California Walnut Commission, Canola Council of Canada, General Mills (Minneapolis, MN, USA), International Nut and Dried Fruit Council, International Pasta Organization, Loblaw Brands Ltd. (Brampton, ON, Canada), Nutrition Foundation of Italy, Oldways Preservation Trust, Paramount Farms (Lost Hills, CA, USA), Peanut Institute, Pulse Canada, Sabra Dipping (White Plains, NY, USA), Saskatchewan Pulse Growers, Sun-Maid (Kingsburg, CA, USA), Tate & Lyle (London, UK), Unilever and White Wave Foods; has served on the scientific advisory board for the International Tree Nut Council, International Pasta Organization, Lantmannen, McCormick Science Institute, Oldways Preservation Trust, Paramount Farms and Pulse Canada; 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; is on the Clinical Practice Guidelines Expert Committee for Nutrition Therapy of the European Association for the Study of Diabetes; and is a director of the Toronto 3D Knowledge Synthesis and Clinical Trials Foundation. D.J.A.J. has received research grants from Heart and Stroke Foundation Grant-in-Aid, Diabetes Canada, Loblaw Companies Ltd. (Brampton, ON, Canada), the Almond Board of California, Soy Nutrition Institute (SNI), and the Canadian Institutes of Health Research (CIHR). He has received in-kind supplies for trials as research support from the Almond Board of California, Walnut Council of California, American Peanut Council, Barilla, Unilever, Unico, Primo, Loblaw Companies, Quaker (Pepsico), Pristine Gourmet, Bunge Limited, Kellogg Canada, and WhiteWave Foods. He has been on the speaker’s panel, served on the scientific advisory board and/or received travel support and/or honoraria for lectures/presentations from Diabetes and Nutrition Study Group (DNSG), Lawson Centre Nutrition Digital Series, 19th Annual Stare-Hegsted Lecture, 2024 Diabetes Canada Conference, Nutritional Fundamentals for Health (NFH)-Nutramedica, Saint Barnabas Medical Center, The University of Chicago, 2020 China Glycemic Index (GI) International Conference, Atlantic Pain Conference, Academy of Life Long Learning, the Almond Board of California, Canadian Agriculture Policy Institute, the Loblaw Companies Ltd., the Griffin Hospital (for the development of the NuVal scoring system), the Coca-Cola Company, Epicure, Danone, Diet Quality Photo Navigation (DQPN), Better Therapeutics (FareWell), Verywell, True Health Initiative (THI), Heali AI Corp, Institute of Food Technologists (IFT), Soy Nutrition Institute (SNI), Herbalife Nutrition Institute (HNI), Herbalife International, Pacific Health Laboratories, Nutritional Fundamentals for Health (NFH), the Soy Foods Association of North America, the Nutrition Foundation of Italy (NFI), the Toronto Knowledge Translation Group (St. Michael’s Hospital), the Canadian College of Naturopathic Medicine, The Hospital for Sick Children, the Canadian Nutrition Society (CNS), and the American Society of Nutrition (ASN). He is a member of the International Carbohydrate Quality Consortium (ICQC). He is invited by the International Diabetes Federation (IDF) to join the committee on diabetes treatment and to take the lead in writing the dietary guidelines for the treatment of diabetes. His wife, Alexandra L Jenkins, is senior scientist of INQUIS Clinical Research Inc. (Clinical Research Organization), his 2 daughters, Wendy Jenkins and Amy Jenkins, have published a vegetarian book that promotes the use of the low glycemic index plant foods advocated here, The Portfolio Diet for Cardiovascular Risk Reduction (Academic Press/Elsevier 2020 ISBN:978-0-12-810510-8) and his sister, Caroline Brydson, received funding through a grant from the St. Michael’s Hospital Foundation to develop a cookbook for one of his studies. L.C. has received research support from the Canadian Institutes of Health Research (CIHR), Protein Industries Canada (a Government of Canada Global Innovation Clusters), The United Soybean Board (USDA soy “Checkoff” program), and the Alberta Pulse Growers Association and honoraria for lectures/presentations from the Arkansas Children’s Hospital and the Physicians Committee for Responsible Medicine. 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, Canadian Institutes of Health Research (CIHR), Diabetes Canada, American Society for Nutrition (ASN), Institute for the Advancement of Food and Nutrition Sciences (IAFNS), The United Soybean Board (USDA soy “Checkoff” program), Protein Industries Canada (a Government of Canada Global Innovation Cluster), Almond Board of California, European Fruit Juice Association, 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 which has received contributions from IFF among other donors), The Plant Milk Fund at the University of Toronto (a fund established by the Karuna Foundation through Vegan Grants), and The Nutrition Trialists Network Fund at the University of Toronto (a fund established by donations from the Calorie Control Council, Physicians Committee for Responsible Medicine, and Login5 Foundation). He has received food donations to support randomized controlled trials from the Almond Board of California, California Walnut Commission, Danone, Mantra Pharma, Terra Delyssa, House Foods, General Mills, WK Kellogg Company, Quaker, Procter & Gamble (P&G), Abbott, and Dairy Farmers of Canada. He has received travel support, speaker fees and/or honoraria from Nestlé (Vevey, Switzerland), Abbott (Abbott Park, IL, USA), General Mills (Minneapolis, MN, USA), International Food Information Council (IFIC), International Sweeteners Association, Calorie Control Council, International Stevia Council, Mantra Pharma Inc. (Laval, QC, Canada), Chinese Institute of Food Science and Technology (CIFST), and Collaborative CME and Research Network (CCRN). He has or has had ad hoc consulting arrangements with Almond Board of California, Perkins Coie LLP (Seattle, WA, USA), Tate & Lyle, Ingredion (Westchester, IL, USA), and Brightseed (San Francisco, CA, USA). He is on the Clinical Practice Guidelines Expert Committees of Diabetes Canada, European Association for the study of Diabetes (EASD), Canadian Cardiovascular Society (CCS), and Obesity Canada/Canadian Association of Bariatric Physicians and Surgeons. He serves as an unpaid member of the Board of Trustees of IAFNS. He is Vice President—Clinical of the Canadian Nutrition Society (CNS), founding member of the International Carbohydrate Quality Consortium (ICQC), Executive Board Member of the Diabetes and Nutrition Study Group (DNSG) of the EASD, and Director of the Toronto 3D Knowledge Synthesis and Clinical Trials foundation. His spouse is an employee of AB InBev (Labatt Breweries of Canada, Toronto, ON, Canada). All other authors report no conflicts of interest.
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