Common Genetic Variants Near SLC2A2 and Glycemic Response to Glimepiride in the GRADE Comparative Effectiveness Clinical Trial

OBJECTIVE Optimizing second-line therapy for type 2 diabetes remains challenging because of interindividual variability in response. Current treatment selection does not consider personal genetic profiles. To address this gap, we conducted a pharmacogenomic genome-wide association study (GWAS) in a randomized comparative effectiveness trial to identify genetic predictors of glycemic response to insulin glargine, glimepiride, liraglutide, and sitagliptin when added to metformin. RESEARCH DESIGN AND METHODS In the Glycemia Reduction Approaches in Type 2 Diabetes: A Comparative Effectiveness Study (GRADE), we performed a GWAS for the time to reach primary (glycated hemoglobin [HbA1c] ≥7%) and secondary (HbA1c >7.5%) metabolic failure. We conducted replication in independent cohorts, performed fine mapping of the top variants near SLC2A2, evaluated them for physiologic impact using oral glucose tolerance testing (OGTT) and response to acute glipizide challenge, and characterized glycemic response to glimepiride in an slc2a2-mutated zebrafish model. RESULTS rs2129019 in SLC2A2 encoding GLUT2 was enriched in African/African American participants and conferred a 38% increased risk of metabolic failure per A allele on glimepiride (P = 1.55 × 10−8). Carriers had impaired β-cell function, evidenced by a lower C-peptide index during OGTT, and diminished glucose-lowering response to acute sulfonylurea challenge. Genetic manipulation in zebrafish confirmed that slc2a2 disruption attenuated the glucose-lowering effect of glimepiride. CONCLUSIONS Genetic variation influences glycemic response to glucose-lowering medications, with SLC2A2 emerging as a genetic factor that modulates sulfonylurea response. These findings warrant further study to evaluate whether low-response allele carriers would benefit from alternative glucose-lowering therapies to advance precision diabetes care.