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SGLT2 Inhibition, Choline Metabolites, and Cardiometabolic Diseases: A Mediation Mendelian Randomization Study
Min Xu1,2, Jie Zheng1,2,3, Tianzhichao Hou1,2
1Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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.
Insights
Sodium-glucose cotransporter 2 (SGLT2) inhibition impacts coronary artery disease (CAD) and type 2 diabetes (T2D) by influencing choline metabolites. These findings reveal potential new pathways for treating these conditions.
Area of Science:
- Cardiovascular Genetics
- Metabolic Disease Research
- Pharmacogenomics
Background:
- Sodium-glucose cotransporter 2 (SGLT2) inhibitors are used to treat type 2 diabetes (T2D) and have shown benefits in coronary artery disease (CAD).
- The precise mechanisms by which SGLT2 inhibitors exert their cardiovascular effects are not fully understood.
- Choline metabolites play crucial roles in various physiological processes, including lipid metabolism and cardiovascular health.
Conclusions:
- SGLT2 inhibition exerts causal effects on specific choline metabolites.
- The cardiovascular benefits of SGLT2 inhibition may be partly mediated through alterations in choline metabolism.
- These findings suggest distinct metabolic pathways through which SGLT2 inhibition influences T2D and CAD.
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