HDL particle concentration mediates protective effect of SGLT2 inhibition on atrial fibrillation

"Our study indicated that genetic variation in SGLT2 inhibition targets was linked with a lower risk of type 2 diabetes (OR 0.63) and AF (0.51)," the researchers reported. "The total concentration of lipoprotein particles might mediate 8% of the effect of SGLT2 inhibition on AF, particularly with the concentration of HDL particles mediating 7.6%." 

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a class of antidiabetic drugs that reduce serum glucose concentration by inhibiting glucose reabsorption in proximal tubules and promoting urinary glucose excretion. Compelling evidence has shown their benefit in improving heart failure, cardiovascular, and renal outcomes. Recent evidence has also suggested their potential to reduce the risk of atrial fibrillation, but the results are controversial and there is no clarity on the underlying metabolic mechanism. Evidence implied that SGLT2 inhibitors have extra beneficial metabolic effects on circulating metabolites beyond glucose control, which might play a role in reducing the AF risk.

Ningjian Wang, Shanghai Jiao Tong University School of Medicine, Shanghai, China, and colleagues, therefore, aimed to investigate the effect of circulating metabolites mediating SGLT2 inhibition in atrial fibrillation by Mendelian randomization (MR).

To evaluate the association of SGLT2 inhibition with AF and the mediation effects of circulating metabolites linking SGLT2 inhibition with AF, the researchers conducted a two-sample (to examine the association between SGLT2 inhibition and AF) and a two-step MR study (to establish the potential metabolic pathway from SGLT2 inhibition to AF through circulating metabolites, specifically blood lipids).

Genetic instruments were identified for SGLT2 inhibition as genetic variants, which were both associated with glycated haemoglobin level (HbA1c) and the expression of the SLC5A2 gene. To validate the selection of genetic instruments, a positive control analysis of genetic instruments was conducted.

The study revealed the following findings:

· Genetically predicted SGLT2 inhibition (per 1 SD decrement in HbA1c) was associated with reduced risk of T2DM (odds ratio [OR] = 0.63) and AF (0.51).

· 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) and the concentration of HDL particles (0.89), with a mediated proportion of 8.03% and 7.59% of the total effect, respectively.

"These findings provided genetic evidence for the mechanisms of SGLT2 inhibition in lowering atrial fibrillation risk and might inform future mechanistic and clinical studies," the authors concluded. 

Reference:

Li, J., Yu, Y., Sun, Y. et al. SGLT2 inhibition, circulating metabolites, and atrial fibrillation: a Mendelian randomization study. Cardiovasc Diabetol 22, 278 (2023). https://doi.org/10.1186/s12933-023-02019-8