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UNLABELLED: Optimizing second-line therapy for type 2 diabetes is challenging due to interindividual variability in response. We conducted a pharmacogenomic genome-wide association study (GWAS) in the Glycemia Reduction Approaches in Type 2 Diabetes: A Comparative Effectiveness (GRADE) Study to identify genetic predictors of glycemic response to insulin glargine, glimepiride, liraglutide, and sitagliptin, when added to metformin in a diverse population. We identified 21 genome-wide significant loci associated with treatment response. rs1905505, a non-coding variant near , the gene encoding the glucose transporter GLUT2, was enriched in Africans/African Americans and conferred a 36% increased risk of treatment failure on glimepiride (=4.83×10). Carriers had impaired β-cell function, evidenced by a lower C-peptide index during OGTT, and diminished glucose-lowering response to an acute sulfonylurea challenge. Genetic manipulation in zebrafish confirmed that disruption attenuates the glucose-lowering effect of glimepiride. In conclusion, genetic variation influences glycemic response to medications, with emerging as a key determinant of sulfonylurea response.CLINICAL TRIAL REGISTRATION NUMBER: NCT01794143.