Write a PREreview

Anti-obesity pharmacotherapy has been transformed by potent GLP-1 and dual GIP/GLP-1 receptor agonists. Semaglutide and tirzepatide produce weight losses of 15–25%, magnitudes previously achievable only through bariatric surgery. Nevertheless, both agents encounter a consistent therapeutic plateau: after initial rapid weight reduction, loss progressively slows and eventually stabilizes despite ongoing treatment. The conventional energy balance model (EBM) attributes this plateau to poorly defined “compensatory metabolic adaptations” but provides no principled mechanistic explanation. In contrast, the mass balance model (MBM) frames the plateau as a predictable physical consequence of one-sided intervention. Current therapies reduce only net mass inflow (NMI) while allowing net mass outflow (NMO) to decline through two mechanisms: passive reduction driven by Torricelli’s Law as body mass decreases, and active down-regulation of the mass clearance coefficient k. I hypothesize that combining an NMI-reducing agent (e.g., a GLP-1 or GIP/GLP-1 receptor agonist) with an NMO-stabilizing or NMO-enhancing agent will achieve greater total weight loss, delay or attenuate the plateau, and improve body composition compared to monotherapy. This dual-action strategy simultaneously targets both sides of the mass balance equation. Promising candidates for the NMO component include SGLT2 inhibitors (via direct glucosuria), activin/myostatin pathway inhibitors (via lean mass preservation), and mitochondrial uncouplers (via increased k through enhanced thermogenesis), with SGLT2 inhibitors currently offering the highest near-term translational potential. This MBM-based rational polypharmacy represents a paradigm shift from viewing obesity as a disorder of energy surplus to treating it as a disorder of mass flow dysregulation. By addressing the previously neglected outflow arm of the mass balance equation, this approach has the potential to overcome the inherent limitations of incretin-based monotherapies and deliver more substantial and durable weight loss.