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Background Dietary guidelines recommend a shift to plant-based diets. Fortified soymilk, a prototypical plant protein food used in the transition to plant-based diets, usually contains added sugars to match the sweetness of cow’s milk and is classified as an ultra-processed food. Whether soymilk can replace minimally processed cow’s milk without the adverse cardiometabolic effects attributed to added sugars and ultra-processed foods remains unclear. We conducted a systematic review and meta-analysis of randomized controlled trials, to assess the effect of substituting soymilk for cow’s milk and its modification by added sugars (sweetened versus unsweetened) on intermediate cardiometabolic outcomes. Methods MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials were searched (through June 2024) for randomized controlled trials of ≥ 3 weeks in adults. Outcomes included established markers of blood lipids, glycemic control, blood pressure, inflammation, adiposity, renal disease, uric acid, and non-alcoholic fatty liver disease. Two independent reviewers extracted data and assessed risk of bias. The certainty of evidence was assessed using GRADE (Grading of Recommendations, Assessment, Development, and Evaluation). A sub-study of lactose versus sucrose outside of a dairy-like matrix was conducted to explore the role of sweetened soymilk which followed the same methodology. Results Eligibility criteria were met by 17 trials ( n  = 504 adults with a range of health statuses), assessing the effect of a median daily dose of 500 mL of soymilk (22 g soy protein and 17.2 g or 6.9 g/250 mL added sugars) in substitution for 500 mL of cow’s milk (24 g milk protein and 24 g or 12 g/250 mL total sugars as lactose) on 19 intermediate outcomes. The substitution of soymilk for cow’s milk resulted in moderate reductions in non-HDL-C (mean difference, − 0.26 mmol/L [95% confidence interval, − 0.43 to − 0.10]), systolic blood pressure (− 8.00 mmHg [− 14.89 to − 1.11]), and diastolic blood pressure (− 4.74 mmHg [− 9.17 to − 0.31]); small important reductions in LDL-C (− 0.19 mmol/L [− 0.29 to − 0.09]) and c-reactive protein (CRP) (− 0.82 mg/L [− 1.26 to − 0.37]); and trivial increases in HDL-C (0.05 mmol/L [0.00 to 0.09]). No other outcomes showed differences. There was no meaningful effect modification by added sugars across outcomes. The certainty of evidence was high for LDL-C and non-HDL-C; moderate for systolic blood pressure, diastolic blood pressure, CRP, and HDL-C; and generally moderate-to-low for all other outcomes. We could not conduct the sub-study of the effect of lactose versus added sugars, as no eligible trials could be identified. Conclusions Current evidence provides a good indication that replacing cow’s milk with soymilk (including sweetened soymilk) does not adversely affect established cardiometabolic risk factors and may result in advantages for blood lipids, blood pressure, and inflammation in adults with a mix of health statuses. The classification of plant-based dairy alternatives such as soymilk as ultra-processed may be misleading as it relates to their cardiometabolic effects and may need to be reconsidered in the transition to plant-based diets. Trial registration ClinicalTrials.gov identifier, NCT05637866.

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.