Effectiveness of Whey Protein Supplementation in Weight Loss Interventions for Patients with Obesity: A Systematic Review

<b>Background</b>: Obesity is traditionally defined by excess fat mass; however, the preservation of fat-free mass (FFM), particularly skeletal muscle, has gained increasing relevance due to its metabolic, endocrine, and functional roles. Weight loss interventions, including hypocaloric diets, pharmacological treatments, and bariatric surgery, are frequently associated with unintended loss of skeletal mass, increasing the risk of sarcopenic obesity and related complications. <b>Objective</b>: This study aimed to systematically evaluate the effectiveness of whey protein supplementation in preserving fat-free mass and muscle-related outcomes in adults with obesity undergoing weight loss interventions. <b>Methods</b>: A systematic review was conducted in accordance with PRISMA guidelines. Randomized controlled trials published in English were identified through searches of PubMed/MEDLINE, CENTRAL, Embase, Scopus, ClinicalTrials.gov, and WHO ICTRP, searched up to September 2025. Eligible studies included adults (>18 years) with obesity receiving whey protein supplementation as part of a hypocaloric diet, compared with placebo or standard interventions. Primary outcomes were changes in fat-free mass assessed by validated methods (DXA, BIA, MRI), while secondary outcomes included body weight, fat mass, metabolic parameters, adherence, and safety. Risk of bias was assessed using the Cochrane RoB 2.0 tool, and certainty of evidence was evaluated with GRADE. The abstract was registered in PROSPERO with code CRD420251069996. There was no funding and no conflicts of interest. <b>Results</b>: Fourteen randomized controlled trials were included. Whey protein supplementation generally supported the maintenance or modest improvement of fat-free mass, particularly when combined with resistance exercise or anabolic-enriched formulations such as leucine or vitamin D. Several trials, however, reported neutral effects, especially in the absence of structured physical activity. Overall, effect estimates ranged from small gains to null or uncertain differences, and the certainty of evidence was frequently downgraded due to limited sample sizes, wide confidence intervals, heterogeneity across interventions and assessment methods, short follow-up periods, and methodological limitations including open-label designs and inconsistent adherence monitoring. <b>Conclusions</b>: Whey protein supplementation may support fat-free mass preservation during weight loss in adults with obesity, particularly as part of a multimodal intervention. Further high-quality trials are needed to define optimal dosing strategies and target populations.