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

Whey protein supplementation generally supported the maintenance or modest improvement of fat-free mass in adults with obesity undergoing weight loss interventions.

• Fourteen randomized controlled trials were included in the systematic review.
• Effect estimates ranged from small gains to null or uncertain differences in fat-free mass.
• Benefits were particularly observed when whey protein was combined with resistance exercise or anabolic-enriched formulations such as leucine or vitamin D.
• Several trials reported neutral effects, especially in the absence of structured physical activity.

The certainty of evidence for whey protein supplementation effects was frequently downgraded due to multiple methodological limitations.

• Limitations included limited sample sizes and wide confidence intervals.
• Heterogeneity across interventions and assessment methods contributed to evidence downgrading.
• Short follow-up periods were identified as a limitation.
• Methodological issues included open-label designs and inconsistent adherence monitoring.

Weight loss interventions in patients with obesity are frequently associated with unintended loss of skeletal mass, increasing the risk of sarcopenic obesity.

• Weight loss interventions considered include hypocaloric diets, pharmacological treatments, and bariatric surgery.
• Loss of skeletal mass during weight loss increases the risk of sarcopenic obesity and related complications.
• Preservation of fat-free mass, particularly skeletal muscle, has gained increasing relevance due to its metabolic, endocrine, and functional roles.

The systematic review was conducted following rigorous methodology including PRISMA guidelines and pre-registration.

• Searches were conducted in PubMed/MEDLINE, CENTRAL, Embase, Scopus, ClinicalTrials.gov, and WHO ICTRP, up to September 2025.
• Only randomized controlled trials published in English were eligible.
• 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).
• 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.

Further high-quality trials are needed to define optimal dosing strategies and target populations for whey protein supplementation in obesity.

• Current evidence is insufficient to establish definitive dosing strategies for whey protein supplementation.
• Target populations that may benefit most from whey protein supplementation remain undefined.
• The review authors conclude that whey protein supplementation may be beneficial particularly as part of a multimodal intervention.