The effect of SGLT2 inhibition on brain-related phenotypes and aging: a drug target Mendelian randomization study

Zhihe Chen; Xueyan Wu; Qianqian Yang; Huiling Zhao; Hui Ying; Haoyu Liu; Chaoyue Wang; Ruizhi Zheng; Hong Lin; Shuangyuan Wang; Mian Li; Tiange Wang; Zhiyun Zhao; Min Xu; Yuhong Chen; Yu Xu; Jieli Lu; Guang Ning; Weiqing Wang; Shan Luo; Shiu Lun Au Yeung; Yufang Bi; Jie Zheng

doi:10.1210/clinem/dgae635

The effect of SGLT2 inhibition on brain-related phenotypes and aging: a drug target Mendelian randomization study

J Clin Endocrinol Metab. 2024 Sep 13:dgae635. doi: 10.1210/clinem/dgae635. Online ahead of print.

Authors

Zhihe Chen^{1

2}, Xueyan Wu^{1

2}, Qianqian Yang^{1

2}, Huiling Zhao³, Hui Ying^{1

2}, Haoyu Liu^{1

2}, Chaoyue Wang⁴, Ruizhi Zheng^{1

2}, Hong Lin^{1

2}, Shuangyuan Wang^{1

2}, Mian Li^{1

2}, Tiange Wang^{1

2}, Zhiyun Zhao^{1

2}, Min Xu^{1

2}, Yuhong Chen^{1

2}, Yu Xu^{1

2}, Jieli Lu^{1

2}, Guang Ning^{1

2}, Weiqing Wang^{1

2}, Shan Luo⁵, Shiu Lun Au Yeung⁵, Yufang Bi^{1

2}, Jie Zheng^{1

2

3}

Affiliations

¹ Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
² Shanghai National Clinical Research Center for metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, Shanghai Digital Medicine Innovation Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
³ MRC Integrative Epidemiology Unit (IEU), Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, Bristol, BS8 2BN, United Kingdom.
⁴ SJTU-Ruijin-UIH Institute for Medical Imaging Technology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁵ School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administration Region, China.

PMID: 39270733
DOI: 10.1210/clinem/dgae635

Abstract

Introduction: Observational study suggested SGLT2 inhibitors might promote healthy aging. However, whether brain-related phenotypes mediate this association. We applied Mendelian randomization (MR) to investigate the effect of SGLT2 inhibition on chronological, 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 (GTEx and eQTLGen data; N=129 to 31,684) and 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 were conducted to explore the associations between SGLT2 inhibition, IDPs, and aging outcomes, 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%CI 1.95 to 11.15), better cognitive function (beta = 0.17, 95%CI 0.03 to 0.31) and higher intelligence (beta = 0.47, 95%CI 0.19 to 0.75). Two-step MR identified two IDPs as mediators linking SGLT2 inhibition with chronological age (total proportion of mediation = 22.6%), where four and five IDPs were mediators for SGLT2 inhibition on cognitive function and intelligence respectively (total proportion of mediation = 61.6% and 68.6% respectively).

Conclusions: 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 similar effect could be observed for users of SGLT2 inhibitors.

Keywords: Mendelian randomization analysis; SGLT2 inhibition; biological age; brain imaging-derived phenotypes; chronological age; cognitive function; intelligence.