{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T13:01:08Z","timestamp":1768568468821,"version":"3.49.0"},"posted":{"date-parts":[[2025,10,8]]},"group-title":"Genetic and Genomic Medicine","reference-count":36,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T00:00:00Z","timestamp":1759881600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,10,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  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\n                  <jats:italic>SLC2A2<\/jats:italic>\n                  , the gene encoding the glucose transporter GLUT2, was enriched in Africans\/African Americans and conferred a 36% increased risk of treatment failure on glimepiride (\n                  <jats:italic>p<\/jats:italic>\n                  =4.83\u00d710). Carriers had impaired \u03b2-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\n                  <jats:italic>slc2a2<\/jats:italic>\n                  disruption attenuates the glucose-lowering effect of glimepiride. In conclusion, genetic variation influences glycemic response to medications, with\n                  <jats:italic>SLC2A2<\/jats:italic>\n                  emerging as a key determinant of sulfonylurea response.\n                <\/jats:p>\n                <jats:p>\n                  Clinical Trial registration number:\n                  <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT01794143\">NCT01794143<\/jats:ext-link>\n                <\/jats:p>","DOI":"10.1101\/2025.10.07.25336827","type":"posted-content","created":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T06:15:22Z","timestamp":1759990522000},"source":"Crossref","is-referenced-by-count":0,"title":["Common genetic variants near\n                  <i>SLC2A2<\/i>\n                  and glycemic response to glimepiride in the GRADE comparative effectiveness clinical trial"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2314-0914","authenticated-orcid":false,"given":"Josephine 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