1717-P: Assessing Type 2 Diabetes and GLP-1 Agonist Response Trajectories with a Proteogenomic Atlas of Disease Progression

Introduction and Objective: To advance precision medicine in Type 2 Diabetes (T2D), we developed the Metabolic Atlas of Progression to Diabetes (MAP-D) to identify proteomic signatures across glycemic stages and evaluate proteins associated with T2D risk and GLP-1 receptor agonist (GLP1RA) response. Methods: MAP-D analyzed proteomic data (2,923 proteins) from a median of 47,963 UK Biobank participants, computing associations with seven metabolic hallmarks (BMI, lipids, blood pressure, HbA1c) across normoglycemia, prediabetes, and T2D. We integrated this with GLP1RA intervention trial data (STEP 1/2) to define “therapeutically intransigent” proteins based on concordant association direction in UKB and treatment-induced change in STEP trials. Results: The atlas revealed 23,290 significant protein-trait associations across stages, with strongest signals for TRIG/HDL ratio and BMI. MAP-D proteins substantially improved prediction of metabolic traits (combined R² up to 0.8; ΔR² up to 0.7) and discriminated patient subpopulations. Critically, “therapeutically intransigent” proteins (e.g., SCARB2, EPHB4) were strongly associated with incident complications: cardiovascular disease, chronic kidney disease, and non-alcoholic fatty liver disease. Conclusion: MAP-D is a resource characterizing T2D progression and residual risk. Intransigent proteins, which are linked to future complications and are targets of approved drugs (e.g., EGFR/nitroglycerin), suggest a strategy for combined GLP1RA therapies to mitigate residual risk and optimize disease management.