Abstract:
Introduction: GLP-1 receptor agonists (GLP-1 RAs) such as semaglutide and tirzepatide have demonstrated significant efficacy in weight reduction and metabolic improvement. However, emerging data suggest that up to 45% of weight loss with semaglutide may derive from fat-free mass (FFM) (Ryan et al., 2025), raising concerns about sarcopenia, resting metabolic rate decline, and functional capacity in long-term obesity treatment. Ketogenic diets (KDs), particularly very low-calorie ketogenic diets (VLCKD), have shown superior FFM preservation when compared to isocaloric or hypocaloric non-ketogenic regimens. This is attributed to the protein-sparing effects of ketosis, hormonal modulation (e.g., insulin suppression, GH elevation), and stabilization of gluconeogenesis (Goday et al., 2016; Barrea et al., 2023). The potential synergy between GLP-1 RAs and ketogenic protocols remains largely unexplored.
Objective: To explore a translational hypothesis: could the metabolic features of ketogenic diets counterbalance the FFM loss observed with GLP-1 RA-induced weight loss?
Methods: A focused synthesis of selected randomized trials and observational studies (2010–2024) involving semaglutide, tirzepatide, and ketogenic nutritional strategies. Key outcomes included FFM changes (measured by DXA), fat distribution, inflammatory markers, and safety data.
Key Findings: According to Ryan et al. (2025), DXA data from a STEP 1 substudy show a mean FFM reduction of −6.92 kg out of −15.3 kg total weight loss with semaglutide. VLCKD interventions preserved FFM significantly better than standard hypocaloric diets (Goday et al., 2016; Barrea et al., 2023), even during rapid weight loss. Mechanistic insights suggest that ketosis supports nitrogen retention and muscle mass preservation during caloric restriction. A 2023 case report documented euglycemic ketoacidosis in a patient on semaglutide without ketogenic diet use, underscoring the need for medical supervision in combined therapies.
Conclusion: Combining GLP-1 RA therapy with a structured ketogenic nutritional approach could represent a novel strategy to maximize fat loss while mitigating adverse changes in body composition. Controlled trials are warranted to assess efficacy, safety, and long-term outcomes. Meanwhile, clinicians should individualize treatment protocols and monitor FFM changes closely.
