The Effect of SGLT2 Inhibition on Brain-related Phenotypes and Aging: A Drug Target Mendelian Randomization Study

Abstract Introduction An observational study suggested sodium-glucose cotransporter 2 (SGLT2) inhibitors might promote healthy aging. However, whether brain-related phenotypes mediate this association is still a question. We applied Mendelian randomization (MR) to investigate the effect of SGLT2 inhibition on chronological age, biological age, and cognition and explore the mediation effects of brain imaging-derived phenotypes (IDPs). Methods We selected genetic variants associated with both expression levels of SLC5A2 (Genotype-Tissue Expression and eQTLGen data; n = 129 to 31 684) and hemoglobin A1c (HbA1c) levels (UK Biobank; n = 344 182) and used them to proxy the effect of SGLT2 inhibition. Aging-related outcomes, including parental longevity (n = 389 166) and epigenetic clocks (n = 34 710), and cognitive phenotypes, including cognitive function (n = 300 486) and intelligence (n = 269 867) were derived from genome-wide association studies. Two-step MR was conducted to explore the associations between SGLT2 inhibition, IDPs, and aging outcomes and cognition. Results SGLT2 inhibition was associated with longer father's attained age [years of life increase per SD (6.75 mmol/mol) reduction in HbA1c levels = 6.21, 95% confidence interval (CI) 1.27-11.15], better cognitive function (beta = .17, 95% CI 0.03-0.31), and higher intelligence (beta = .47, 95% CI 0.19-0.75). Two-step MR identified 2 IDPs as mediators linking SGLT2 inhibition with chronological age (total proportion of mediation = 22.6%), where 4 and 5 IDPs were mediators for SGLT2 inhibition on cognitive function and intelligence, respectively (total proportion of mediation = 61.6% and 68.6%, respectively). Conclusion Our study supported that SGLT2 inhibition increases father's attained age, cognitive function, and intelligence, which was mediated through brain images of different brain regions. Future studies are needed to investigate whether a similar effect could be observed for users of SGLT2 inhibitors.