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SGLT2 inhibition, circulating metabolites, and atrial fibrillation: a Mendelian randomization study

BACKGROUND: Sodium-glucose cotransporter 2 (SGLT2) inhibitors have shown promise in reducing the risk of atrial fibrillation (AF). However, the results are controversial and the underlying metabolic mechanism remains unclear. Emerging evidence implied that SGLT2 inhibitors have extra beneficial meta...

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Detalles Bibliográficos
Autores principales: Li, Jiang, Yu, Yuefeng, Sun, Ying, Yu, Bowei, Tan, Xiao, Wang, Bin, Lu, Yingli, Wang, Ningjian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10583416/
https://www.ncbi.nlm.nih.gov/pubmed/37848934
http://dx.doi.org/10.1186/s12933-023-02019-8
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author Li, Jiang
Yu, Yuefeng
Sun, Ying
Yu, Bowei
Tan, Xiao
Wang, Bin
Lu, Yingli
Wang, Ningjian
author_facet Li, Jiang
Yu, Yuefeng
Sun, Ying
Yu, Bowei
Tan, Xiao
Wang, Bin
Lu, Yingli
Wang, Ningjian
author_sort Li, Jiang
collection PubMed
description BACKGROUND: Sodium-glucose cotransporter 2 (SGLT2) inhibitors have shown promise in reducing the risk of atrial fibrillation (AF). However, the results are controversial and the underlying metabolic mechanism remains unclear. Emerging evidence implied that SGLT2 inhibitors have extra beneficial metabolic effects on circulating metabolites beyond glucose control, which might play a role in reducing the risk of AF. Hence, our study aimed to investigate the effect of circulating metabolites mediating SGLT2 inhibition in AF by Mendelian randomization (MR). METHODS: A two-sample and two-step MR study was conducted to evaluate the association of SGLT2 inhibition with AF and the mediation effects of circulating metabolites linking SGLT2 inhibition with AF. Genetic instruments for SGLT2 inhibition were identified as genetic variants, which were both associated with the expression of SLC5A2 gene and glycated hemoglobin level (HbA1c). Positive control analysis on type 2 diabetes mellitus (T2DM) was conducted to validate the selection of genetic instruments. RESULTS: Genetically predicted SGLT2 inhibition (per 1 SD decrement in HbA1c) was associated with reduced risk of T2DM (odds ratio [OR] = 0.63 [95% CI 0.45, 0.88], P = 0.006) and AF (0.51 [0.27, 0.97], P = 0.039). Among 168 circulating metabolites, two metabolites were both associated with SGLT2 inhibition and AF. The effect of SGLT2 inhibition on AF through the total concentration of lipoprotein particles (0.88 [0.81, 0.96], P = 0.004) and the concentration of HDL particles (0.89 [0.82, 0.97], P = 0.005), with a mediated proportion of 8.03% (95% CI [1.20%, 14.34%], P = 0.010) and 7.59% ([1.09%, 13.34%], P = 0.011) of the total effect, respectively. CONCLUSIONS: This study supported the association of SGLT2 inhibition with a reduced risk of AF. The total concentration of lipoprotein particles and particularly the concentration of HDL particles might mediate this association. Further mechanistic and clinical studies research are needed to understand the mediation effects of circulating metabolites especially blood lipids in the association between SGLT2 inhibition and AF. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12933-023-02019-8.
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spelling pubmed-105834162023-10-19 SGLT2 inhibition, circulating metabolites, and atrial fibrillation: a Mendelian randomization study Li, Jiang Yu, Yuefeng Sun, Ying Yu, Bowei Tan, Xiao Wang, Bin Lu, Yingli Wang, Ningjian Cardiovasc Diabetol Research BACKGROUND: Sodium-glucose cotransporter 2 (SGLT2) inhibitors have shown promise in reducing the risk of atrial fibrillation (AF). However, the results are controversial and the underlying metabolic mechanism remains unclear. Emerging evidence implied that SGLT2 inhibitors have extra beneficial metabolic effects on circulating metabolites beyond glucose control, which might play a role in reducing the risk of AF. Hence, our study aimed to investigate the effect of circulating metabolites mediating SGLT2 inhibition in AF by Mendelian randomization (MR). METHODS: A two-sample and two-step MR study was conducted to evaluate the association of SGLT2 inhibition with AF and the mediation effects of circulating metabolites linking SGLT2 inhibition with AF. Genetic instruments for SGLT2 inhibition were identified as genetic variants, which were both associated with the expression of SLC5A2 gene and glycated hemoglobin level (HbA1c). Positive control analysis on type 2 diabetes mellitus (T2DM) was conducted to validate the selection of genetic instruments. RESULTS: Genetically predicted SGLT2 inhibition (per 1 SD decrement in HbA1c) was associated with reduced risk of T2DM (odds ratio [OR] = 0.63 [95% CI 0.45, 0.88], P = 0.006) and AF (0.51 [0.27, 0.97], P = 0.039). Among 168 circulating metabolites, two metabolites were both associated with SGLT2 inhibition and AF. The effect of SGLT2 inhibition on AF through the total concentration of lipoprotein particles (0.88 [0.81, 0.96], P = 0.004) and the concentration of HDL particles (0.89 [0.82, 0.97], P = 0.005), with a mediated proportion of 8.03% (95% CI [1.20%, 14.34%], P = 0.010) and 7.59% ([1.09%, 13.34%], P = 0.011) of the total effect, respectively. CONCLUSIONS: This study supported the association of SGLT2 inhibition with a reduced risk of AF. The total concentration of lipoprotein particles and particularly the concentration of HDL particles might mediate this association. Further mechanistic and clinical studies research are needed to understand the mediation effects of circulating metabolites especially blood lipids in the association between SGLT2 inhibition and AF. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12933-023-02019-8. BioMed Central 2023-10-17 /pmc/articles/PMC10583416/ /pubmed/37848934 http://dx.doi.org/10.1186/s12933-023-02019-8 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Li, Jiang
Yu, Yuefeng
Sun, Ying
Yu, Bowei
Tan, Xiao
Wang, Bin
Lu, Yingli
Wang, Ningjian
SGLT2 inhibition, circulating metabolites, and atrial fibrillation: a Mendelian randomization study
title SGLT2 inhibition, circulating metabolites, and atrial fibrillation: a Mendelian randomization study
title_full SGLT2 inhibition, circulating metabolites, and atrial fibrillation: a Mendelian randomization study
title_fullStr SGLT2 inhibition, circulating metabolites, and atrial fibrillation: a Mendelian randomization study
title_full_unstemmed SGLT2 inhibition, circulating metabolites, and atrial fibrillation: a Mendelian randomization study
title_short SGLT2 inhibition, circulating metabolites, and atrial fibrillation: a Mendelian randomization study
title_sort sglt2 inhibition, circulating metabolites, and atrial fibrillation: a mendelian randomization study
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10583416/
https://www.ncbi.nlm.nih.gov/pubmed/37848934
http://dx.doi.org/10.1186/s12933-023-02019-8
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