Abstract 11650: Cardiometabolic Disease Protein Signatures and Response to GLP-1 Receptor Agonist in the EXSCEL Clinical Trial

Introduction: Recent type 2 diabetes (T2D) therapeutics have pleiotropic benefits. High throughput proteomic assays offer opportunities to systematically analyze T2D-related cardiometabolic traits and drug-related effects. Methods: The Exenatide Study of Cardiovascular Event Lowering (EXSCEL) trial randomized patients with T2D to once-weekly exenatide (EQW) versus placebo. This biomarker substudy of 5205 participants performed plasma proteomic profiling on baseline and 1-year samples using an aptamer-based platform. Changes in nine protein-imputed cardiometabolic traits were compared between treatment groups. In exploratory analyses, proteomic cardiovascular (CV) risk was stratified in individuals based on use of open label “drop-in” SGLT-2 inhibitors during follow-up. Results: Proteomic signatures for impaired glucose tolerance, body fat, and visceral fat decreased more in the EQW group compared with placebo (adjusted p<0.05), partially consistent with EQW-induced weight loss ( Figure ). Protein-imputed resting energy rate, cardiorespiratory fitness, and lean body mass also decreased to a greater extent in the EQW group. Proteomic CV risk increased in both groups over one year but increased less in the EQW group (0.8% vs. 2.3%, adjusted p<0.01). Individuals predicted at baseline to be at high CV risk had significantly lower observed CV event rates if they received “drop-in” SGLT-2 inhibitors (p<0.05). Conclusion: Leveraging EXSCEL, a large-scale clinical trial of a GLP1-receptor agonist, this biomarker substudy uses proteomic signatures to demonstrate pleiotropic drug effects related to cardiometabolic traits. Further, proteomic CV risk increased to a lesser extent in individuals randomized to EQW, suggesting that EQW has beneficial effects influencing cardiovascular risk directly or indirectly through these proteomic pathways.