Abstract:
Introduction: GLP-1 receptor agonists (GLP-1 RAs) such as semaglutide have demonstrated impressive efficacy in inducing weight loss and improving metabolic health. However, recent reviews suggest that approximately 45% of the total weight loss under semaglutide may derive from fat-free mass (FFM), raising concerns regarding long-term functional and metabolic consequences. Ketogenic diets (KDs), particularly Very Low Energy Ketogenic Therapy (VLEKT), have shown superior preservation of FFM compared to standard hypocaloric regimens, due to their protein-sparing nature and ability to modulate insulin levels and gluconeogenesis (Goday et al., 2016). This suggests a potential synergistic application of KDs with GLP-1 RAs to preserve lean body mass during pharmacological weight loss.
Objective: To review existing clinical literature on body composition changes induced by GLP-1 RAs and ketogenic diets, and to hypothesize a combined approach that minimizes FFM loss during obesity treatment.
Methods: Synthesis of selected findings from clinical trials and observational studies published between 2010 and 2024, focusing on semaglutide, tirzepatide, and ketogenic protocols. Outcomes of interest included fat-free mass, fat mass, body fat distribution, and metabolic biomarkers.
Key Findings: According to Ryan et al. (2025), analyses of DXA data from a subset of STEP 1 participants revealed that semaglutide treatment resulted in a mean loss of −6.92 kg of FFM out of −15.3 kg of total weight loss. In contrast, VLEKT interventions preserved FFM significantly better than standard diets (Goday et al., 2016; Barrea et al., 2023). The "protein-sparing" effect of ketosis has been linked to hormonal adaptations (e.g., reduced insulin, increased GH) and preserved muscle protein catabolism. A case report in 2023 described an episode of euglycemic ketoacidosis in a non-diabetic patient treated with semaglutide, unrelated to ketogenic diet use, but suggesting the need for caution and monitoring in potential combined protocols.
Conclusion: A strategic integration of ketogenic nutrition with GLP-1 receptor agonist therapy may represent a promising avenue for sustained fat loss while preserving FFM. Clinical trials are needed to validate this hypothesis and define safe, personalized intervention models. Until then, caution is advised when combining these approaches.
Keywords: GLP-1 receptor agonists, ketogenic diet, semaglutide, lean mass, VLEKT, VLCKD, obesity
