Key result
Genetically predicted SGLT2 inhibition was associated with a reduced risk of atrial fibrillation (OR 0.51), an effect partially mediated by the total concentration of lipoprotein particles.
Why the study?
Whether SGLT2 inhibitors reduce atrial fibrillation risk remains controversial, and the underlying metabolic mechanisms mediating this potential effect are unclear.
Does genetically predicted SGLT2 inhibition reduce the risk of atrial fibrillation, and is this effect mediated by circulating metabolites?
Observational
Mendelian randomization
Does genetically predicted SGLT2 inhibition reduce the risk of atrial fibrillation, and is this effect mediated by circulating metabolites?
Odds Ratio: 0.51 (95% CI 0.27–0.97)
p-value: p=0.039
Genetically predicted SGLT2 inhibition is associated with a reduced risk of atrial fibrillation, an effect that may be partially mediated by increases in HDL particle concentrations.
MR evidence links lipoprotein particles to SGLT2-AF protection; leaves open whether metabolite modulation alters AF risk in trials.
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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Li et al. (2023) conducted an observational in Atrial fibrillation. Genetically predicted SGLT2 inhibition vs. Lack of genetically predicted SGLT2 inhibition was evaluated on Atrial fibrillation (OR 0.51, 95% CI 0.27, 0.97, p=0.039). Genetically predicted SGLT2 inhibition was associated with a reduced risk of atrial fibrillation (OR 0.51), an effect partially mediated by the total concentration of lipoprotein particles.
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