Familial Renal Glucosuria and Potential Pharmacogenetic Impact on Sodium-Glucose Cotransporter-2 Inhibitors

Key Points A significant knowledge gap exists in SLC5A2 's role in familial renal glycosuria and sodium-glucose cotransporter-2 inhibitors' efficacy. Two percent of individuals in the All-of-Us cohort harbor rare genetic variants in SLC5A2 , potentially increasing the risk of familial renal glycosuria. Our trial suggests differential responses to sodium-glucose cotransporter-2 inhibitors in individuals with rare SLC5A2 alleles compared with wild types. Background Renal glucosuria is a rare inheritable trait caused by loss-of-function variants in the gene that encodes sodium-glucose cotransporter-2 (SGLT2) ( i.e ., SLC5A2 ). The genetics of renal glucosuria is poorly understood, and even less is known on how loss-of-function variants in SLC5A2 may affect response to SGLT2 inhibitors, a new class of medication gaining popularity to treat diabetes by artificially inducing glucosuria. Methods We used two biobanks that link genomic with electronic health record data to study the genetics of renal glucosuria. This included 245,394 participants enrolled in the All of Us Research Program and 11,011 enrolled in Marshfield Clinic's Personalized Research Project (PMRP). Association studies in All of Us and PMRP identified ten variants that reached an experiment-wise Bonferroni threshold in either cohort, of which nine were novel. PMRP was further used as a recruitment source for a prospective SGLT2 pharmacogenetic trial. During a glucose tolerance test, the trial measured urine glucose concentrations in 15 SLC5A2 variant–positive individuals and 15 matched wild types with and without an SGLT2 inhibitor. Results This trial demonstrated that carriers of SLC5A2 risk variants may be more sensitive to SGLT2 inhibitors compared with wild types ( P = 0.075). On the basis of population data, 2% of an ethnically diverse population carried rare variants in SLC5A2 and are at risk of renal glucosuria. Conclusions As a result, 2% of individuals being treated with SGLT2 inhibitors may respond differently to this new class of medication compared with the general population, suggesting that a larger investigation into SLC5A2 variants and SGLT2 inhibitors is needed.