SGLT2 inhibition, high-density lipoprotein cholesterol and aortic aneurysm: A drug-target Mendelian randomization...

The causal effect of sodium-glucose cotransporter 2 (SGLT2) inhibition on aortic aneurysm (AA), as well as the underlying lipid metabolism, remain largely unexplored.

We extracted genetic variants within the cis-region of the SLC5A2 gene from the genome-wide association study of hemoglobin A1c (HbA1c) to proxy the effects of SGLT2 inhibition. Two-sample Mendelian randomization (MR) was subsequently performed to evaluate the causal effect of SGLT2 inhibition on type 2 diabetes mellitus (T2DM, serving as a positive control) and AA. Two-step mediation MR was further implemented to elucidate the potential mediating role of lipid metabolism in the pathway linking SGLT2 inhibition to AA. We found genetically predicted SGLT2 inhibition (per 1 SD decrease in HbA1c) was associated with reduced risk of T2DM (OR: 0.62, 95% CI: 0.45, 0.86, P_FDR = 0.008) and AA (OR: 0.84, 95% CI: 0.77, 0.92, P_FDR = 7.36 × 10^-4). Subgroup analysis indicated that SGLT2 inhibition could lower the incidence of abdominal AA (OR: 0.90, 95% CI: 0.82, 0.99, P_FDR = 0.024) and thoracic AA (OR: 0.87, 95% CI: 0.78, 0.98, P_FDR = 0.024). Mediation analysis suggested that high-density lipoprotein cholesterol (HDL-C) mediated the effect of SGLT2 inhibition on AA and abdominal AA, with a mediated proportion of 3.55% (95% CI: 1.38%, 5.72%, P = 0.001) and 6.14% (95% CI: 2.63%, 9.64%, P = 5.60 × 10^-4), respectively.

Our study demonstrated that HDL-C could partially mediate the protective effect of SGLT2 inhibition on AA, particularly on abdominal AA.