SGLT2 Inhibition, Choline Metabolites, and Cardiometabolic Diseases: A Mediation Mendelian Randomization Study

Min Xu; Jie Zheng; Tianzhichao Hou; Hong Lin; Tiange Wang; Shuangyuan Wang; Jieli Lu; Zhiyun Zhao; Mian Li; Yu Xu; Guang Ning; Yufang Bi; Weiqing Wang

doi:10.2337/dc22-0323

SGLT2 Inhibition, Choline Metabolites, and Cardiometabolic Diseases: A Mediation Mendelian Randomization Study

Diabetes Care. 2022 Nov 1;45(11):2718-2728. doi: 10.2337/dc22-0323.

Authors

Min Xu^{1

2}, Jie Zheng^{1

2

3}, Tianzhichao Hou^{1

2}, Hong Lin^{1

2}, Tiange Wang^{1

2}, Shuangyuan Wang^{1

2}, Jieli Lu^{1

2}, Zhiyun Zhao^{1

2}, Mian Li^{1

2}, Yu Xu^{1

2}, Guang Ning^{1

2}, Yufang Bi^{1

2}, Weiqing Wang^{1

2}

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 People's Republic of China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
³ MRC Integrative Epidemiology Unit, Bristol Medical School, University of Bristol, Bristol, U.K.

Abstract

Objective: To investigate the causal role of choline metabolites mediating sodium-glucose cotransporter 2 (SGLT2) inhibition in coronary artery disease (CAD) and type 2 diabetes (T2D) using Mendelian randomization (MR).

Research design and methods: A two-sample two-step MR was used to determine 1) causal effects of SGLT2 inhibition on CAD and T2D; 2) causal effects of three choline metabolites, total choline, phosphatidylcholine, and glycine, on CAD and T2D; and 3) mediation effects of these metabolites. Genetic proxies for SGLT2 inhibition were identified as variants in the SLC5A2 gene that were associated with both levels of gene expression and hemoglobin A1c. Summary statistics for metabolites were from UK Biobank, CAD from CARDIoGRAMplusC4D (Coronary ARtery DIsease Genome wide Replication and Meta-analysis [CARDIoGRAM] plus The Coronary Artery Disease [C4D] Genetics) consortium, and T2D from DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) and the FinnGen study.

Results: SGLT2 inhibition (per 1 SD, 6.75 mmol/mol [1.09%] lowering of HbA1c) was associated with lower risk of T2D and CAD (odds ratio [OR] 0.25 [95% CI 0.12, 0.54], and 0.51 [0.28, 0.94], respectively) and positively with total choline (β 0.39 [95% CI 0.06, 0.72]), phosphatidylcholine (0.40 [0.13, 0.67]), and glycine (0.34 [0.05, 0.63]). Total choline (OR 0.78 [95% CI 0.68, 0.89]) and phosphatidylcholine (OR 0.81 [0.72, 0.91]) were associated with T2D but not with CAD, while glycine was associated with CAD (0.94 [0.91, 0.98]) but not with T2D. Mediation analysis showed evidence of indirect effect of SGLT2 inhibition on T2D through total choline (0.91 [0.83, 0.99]) and phosphatidylcholine (0.93 [0.87, 0.99]) with a mediated proportion of 8% and 5% of the total effect, respectively, and on CAD through glycine (0.98 [0.96, 1.00]) with a mediated proportion of 2%. The results were well validated in at least one independent data set.

Conclusions: Our study identified the causal roles of SGLT2 inhibition in choline metabolites. SGLT2 inhibition may influence T2D and CAD through different choline metabolites.

Publication types

Meta-Analysis
Research Support, Non-U.S. Gov't

MeSH terms

Choline
Coronary Artery Disease* / genetics
Diabetes Mellitus, Type 2* / metabolism
Genome-Wide Association Study / methods
Glycine / genetics
Humans
Mendelian Randomization Analysis / methods
Phosphatidylcholines
Polymorphism, Single Nucleotide
Risk Factors
Sodium-Glucose Transporter 2 Inhibitors* / therapeutic use

Substances

Choline
Glycine
Phosphatidylcholines
Sodium-Glucose Transporter 2 Inhibitors

Abstract

Publication types

MeSH terms

Substances

Grants and funding