36-OR: Modulation of Cardiorenal Benefits for GLP-1RAs Treatment by GLP1R Genetic Variants

Introduction: While previous research has investigated the influence of patients’ clinical characteristics on GLP-1RAs’ treatment benefits, the potential influence of genetic variants, remains insufficiently explored. Methods: We included 3951 GLP-1 RAs new users from the All of Us program (2005-2022), and propensity-matched to a comparison group who started other second-line anti-diabetes medications. We examined 15 genetic loci significantly associated with GLP1R gene expression. Intention-to-treat analysis was performed to examine the effect of GLP-1RAs treatment with acute myocardial infarction (AMI) and acute kidney injury (AKI) using Cox proportional hazards models. Genetic variants were included as an interaction. Results: Significant larger reductions in AMI risk were observed for eight variants (rs9296276, rs6923761, rs9296280, rs13216992, rs35887128, rs7753618, rs10305491) with GLP-1RAs treatment; and four unique variants (rs2268650, rs880347, rs5875653, rs10305439) were linked to decreased AKI risk with GLP-1RAs treatment. Polygenic scores utilizing these variants showed that higher scores were associated with higher GLP-1RA benefits in reducing AMI (high score: -59.1% vs Low: -14.4%) and AKI (high: -26.3% vs low: +36.3%) risk. Conclusion: Our results and polygenic scores offer a pathway towards more personalization for decisions regarding GLP-1 RAs use in clinical practice. Disclosure Q. Xue: None. P. Li: None. F.J. Pasquel: Research Support; Tandem Diabetes Care, Inc., Insulet Corporation, Dexcom, Inc., Ideal Medical Technologies, Novo Nordisk. Consultant; Dexcom, Inc., Medscape. L.S. Phillips: Other Relationship; Diasyst, Inc. Research Support; Kowa Pharmaceuticals America, Inc., Janssen Pharmaceuticals, Inc., AbbVie Inc., Novo Nordisk, GlaxoSmithKline plc, Abbott, Sanofi-Aventis U.S., Pfizer Inc. D. Liang: None. K. Narayan: None. G. Umpierrez: Research Support; Abbott, Bayer Inc., Dexcom, Inc., AstraZeneca. Advisory Panel; Dexcom, Inc. M.K. Ali: Advisory Panel; Eli Lilly and Company. H. Shao: Consultant; Eli Lilly and Company.