Dose-Response Profiles in Incretin and Multi-Agonist Obesity Pharmacotherapy.

Abstract

Incretin and multi-agonist therapies have transformed obesity pharmacotherapy, but dose selection remains less mature than efficacy assessment. This critical narrative review examines nonlinear relationships among administered dose, systemic exposure, weight and cardiometabolic benefit, gastrointestinal tolerability, treatment persistence, and maintenance. Across established and newer programs, average efficacy generally increases with dose, yet incremental gains may narrow at higher exposure while adverse-event burden and discontinuation can increase. The maturity of evidence is heterogeneous, and later-stage programs should not be interpreted as clinically equivalent to agents supported mainly by earlier-phase dose-ranging data. Moreover, an "optimal dose" is not an endpoint-independent quantity: the exposure most appropriate for weight loss may differ from that relevant to glycemic control, cardiovascular benefit, body composition, tolerability, or maintenance. We therefore distinguish nominal dose from exposure and present response-guided titration as a hypothesis-generating framework for prospective testing, not as an evidence-based dosing algorithm. Existing continuation and withdrawal studies support the importance of ongoing pharmacological treatment after successful weight loss but do not establish a minimum or optimal de-intensified maintenance dose. Future trials should jointly model efficacy, safety, body composition, patient-reported outcomes, pharmacokinetics, and discontinuation to test objective-specific, patient-level dosing strategies.