An Integrated Analysis of GLP-1R Agonist Mechanisms: Addressing Study Variations in Heterogeneous Cell Systems

Abstract

Experimental cell systems support the development of pharmacological therapies such as glucagon-like peptide-1 receptor agonists (GLP-1RAs). However, their utility in drug discovery is limited due to study variability, which complicates formation of unified conclusions based on all available data. To address this, we conducted a comprehensive analysis of the GLP-1RA exenatide, incorporating 16 new and five pre-existing mono- or co-culture studies of human liver and pancreatic models. We employed a new pragmatic model-based approach designed to handle the common situation of heterogeneous in vitro datasets with few replicates per condition. All studies are jointly explained (disagreement<{chi}{superscript 2}-limit; 542<732), thereby providing a unified conclusion based on all studies. This work links in vitro biology to clinically relevant mechanisms, such as exenatides effect on glucose-insulin interplay, and predicts previously undescribed inter-study variabilities. Independent validation confirms predictive performance (64<83). Our new integrative approach enhances the utility of experimental cell systems in preclinical drug discovery.