SGLT2 inhibition, circulating biomarkers, and Alzheimer's disease: A Mendelian randomization study

Background Sodium-glucose cotransporter 2 (SGLT2) inhibitors is a novel category of medications for diabetes, exhibiting neuroprotective potential. However, evidence regarding whether the use of SGLT2 inhibitors effectively reduces the risk of Alzheimer's disease (AD) remains unclear. Objective Our study employed Mendelian randomization (MR) analysis to investigate potential causal relationships between SGLT2 inhibition, metabolites, and AD. Methods In our research, we used a two-sample MR method to explore the link between SGLT2 inhibitor use and AD, addressing both its late-onset and early-onset forms. Furthermore, we executed a two-step MR analysis to explore how circulating metabolites, primarily endogenous in nature due to SGLT2 inhibition, mediate the relationship between SGLT2 inhibition and AD. The genetic instruments for SGLT2 inhibition were pinpointed through their association with SLC5A2 gene expression and the decreased glycated hemoglobin (HbA1c) levels. Results Genetic analysis indicated that SGLT2 inhibition, which effectively reduces HbA1c by enhancing renal glucose excretion and improving glycemic control, was associated with a lower likelihood of developing AD for every 1 SD decrease in HbA1c (OR = 0.48, [0.36, 0.63], p < 0.001). Our MR analysis revealed that SGLT2 inhibition significantly affected 27 of the 123 metabolites examined, adhering to a Bonferroni correction threshold (p < 4.06 × 10-4). Among these 27 significant metabolites, citrate was also associated with AD, showing a significant association (0.81 [0.79, 0.83], p < 0.001). Conclusions The study provides strong evidence linking SGLT2 inhibition with a lower AD risk, highlighting citrate's potential mediating role for subsequent clinical research.