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

作者：Zhihe Chen, Xueyan Wu, Qianqian Yang, Huiling Zhao, Hui Ying, Haoyu Liu, Chaoyue Wang, Ruizhi Zheng, Lin Hong, Shuangyuan Wang, Mian Li, Tiange Wang, Zhiyun Zhao, Min Xu, Yu‐Hong Chen, Yu Xu, Jieli Lu, Guang Ning, Weiqing Wang, Shan Luo, Shiu Lun Au Yeung, Yufang Bi, Jie Zheng · 发表于：The Journal of Clinical Endocrinology & Metabolism · 年份：2024 · DOI：10.1210/clinem/dgae635 · 被引用次数：10 · 研究领域：Diabetes Treatment and Management、Genetic Associations and Epidemiology、Pancreatic function and diabetes

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 media...