Positioning Incretin-Based and Next-Generation Obesity Management Medications: A Methodological Framework for a...

The obesity pharmacotherapy landscape is evolving rapidly, with several approved incretin-based therapies and an expanding pipeline of investigational compounds targeting multiple metabolic pathways. Conventional evidence syntheses often struggle to accommodate differences in dose selection, treatment duration and stage of clinical development. To describe a methodological framework for a series of systematic reviews and network meta-analyses aimed at comparing approved and investigational obesity management medications (OMMs).

This article presents the methodological framework for a series of systematic reviews and network meta-analyses that will be conducted according to PRISMA 2020, PRISMA-NMA and PRISMA-P recommendations. Separate reviews and network meta-analyses will be performed for individual pharmacological classes of OMMs. Treatment nodes will be defined as molecule-dose combinations, selecting the highest approved dose for marketed therapies and the highest tested dose for investigational agents. Eligible studies will include randomised Phase 1-4 trials conducted in adults with overweight or obesity, with or without Type 2 diabetes. The primary outcome will be percentage total body weight loss at approximately 24-26 weeks. Risk of bias and certainty of evidence will be assessed using RoB 2 and CINeMA.

The framework identifies 40 obesity investigational molecules that have completed at least Phase 1 development and groups them into 13 major mechanistic classes and nine approved therapies for the treatment of obesity. The present framework, therefore, encompasses 49 molecules which will serve as candidate interventions for future class-specific network meta-analyses.

This paper presents a dose-informed methodological framework for future evidence syntheses in obesity pharmacotherapy, supporting comparative evaluation and contextual positioning of next-generation OMMs.

PROSPERO-CRD420261425340.