Common genetic variants near SLC2A2 and glycemic response to glimepiride in the GRADE comparative effectiveness clinical trial.

Li JH, Szczerbinski L, Tripputi M, Liu H, Nam S, Mujica E, Emmanouilidou A, Wangden TY, Citko-Rojewska A, Konopka P, Czajkowski M, Huerta-Chagoya A, Vora M, Leong A, Meigs JB, Ng MY, Loos RJF, Pigeyre M, Gerstein HC, Moura FA, Lai YP, Bhatt DL, Marston NA, Ruff CT, Sabatine MS, Dawed AY, Pearson ER, Satin LS, den Hoed M, Kretowski A, Kahn SE, Younes N, Mercader JM, Florez JC

medRxiv - (-) - [2025-10-08; online 2025-10-08]

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 SLC2A2, the gene encoding the glucose transporter GLUT2, was enriched in Africans/African Americans and conferred a 36% increased risk of treatment failure on glimepiride (p=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 slc2a2 disruption attenuates the glucose-lowering effect of glimepiride. In conclusion, genetic variation influences glycemic response to medications, with SLC2A2 emerging as a key determinant of sulfonylurea response. NCT01794143.

PubMed 41282760

DOI 10.1101/2025.10.07.25336827

Crossref 10.1101/2025.10.07.25336827

pmc: PMC12632647
pii: 2025.10.07.25336827
ClinicalTrials.gov: NCT01794143