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Cardiovascular Diabetology

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Open Access 01-12-2023 | Atrial Fibrillation | Research

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

Authors: Jiang Li, Yuefeng Yu, Ying Sun, Bowei Yu, Xiao Tan, Bin Wang, Yingli Lu, Ningjian Wang

Published in: Cardiovascular Diabetology | Issue 1/2023

Abstract

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.

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Title: SGLT2 inhibition, circulating metabolites, and atrial fibrillation: a Mendelian randomization study
Authors: Jiang Li
Yuefeng Yu
Ying Sun
Bowei Yu
Xiao Tan
Bin Wang
Yingli Lu
Ningjian Wang
Publication date: 01-12-2023
Publisher: BioMed Central
Keyword: Atrial Fibrillation
Published in: Cardiovascular Diabetology / Issue 1/2023
Electronic ISSN: 1475-2840
DOI: https://doi.org/10.1186/s12933-023-02019-8

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