174-OR: Genetic Variation in GLP-1R Modify the Risk of Hypoglycemia in Response to Intensive Glycemic Control in Adults with Type 2 Diabetes

Introduction: Hypoglycemia is a potential side effect of Intensive Glycemic Control (IGC) in diabetes management. We aimed to investigate whether individuals with certain GLP1R gene variations were at greater hypoglycemia risk with IGC. Methods: A dynamic cohort design with time-varying exposures was employed using electronic health records linked to survey data from 8,848 individuals in the All-of-Us database. Subjects with type 2 diabetes and antidiabetic medication use could transition between the IGC exposure group (A1c 7.0%) and the moderate glycemic control group (A1c 7%-8.5%) during follow-up or were censored at their last visit, death, end of the study, or if A1c exceeded 8.5%. Per-protocol analysis was conducted using mixed-effects Cox proportional regression models, adjusting for demographics and a comprehensive set of time-varying variables, including disease histories, lab values, medications, and patient-reported conditions. Results: During a median follow-up period of 6.2 years, we documented 841 incident cases of hypoglycemia (incidence rate:1.34 per 100 person-years). Compared to the moderate GC group, the IGC group had a higher hypoglycemia risk (hazard ratio (HR): 1.06, 95% CI:1.00-1.12). Thirteen out of 15 GLP1R genetic variants significantly modified such risk, demonstrating a notable variation in risk across different genotypes, with HR ranging from 0.46 to 1.19. Combining these variants in a polygenic risk score showed that higher scores were associated with higher IGC-associated hypoglycemia risk (high score: HR 1.27, 95% CI 1.13-1.43 vs Low score: HR 0.57, 95% CI [0.43, 0.77). Sensitivity analyses excluding all GLP-1RA users yielded consistent results. Conclusion: Our findings indicate that GLP1R variants play a modulating role in IGC-associated hypoglycemia risk, independent of GLP-1RA use. This effect suggests the prominent role of GLP1R genes in safe glucose-lowering among patients with type 2 diabetes. Disclosure Q. Xue: None. P. Li: None. R. Jagannathan: None. F.J. Pasquel: Research Support; Tandem Diabetes Care, Inc., Insulet Corporation, Dexcom, Inc., Ideal Medical Technologies, Novo Nordisk. Consultant; Dexcom, Inc., Medscape. G. Umpierrez: Research Support; Abbott, Bayer Inc., Dexcom, Inc., AstraZeneca. Advisory Panel; Dexcom, Inc. 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. M.K. Ali: Advisory Panel; Eli Lilly and Company. H. Shao: Consultant; Eli Lilly and Company.