SGLT1 and SGLT2 inhibition, circulating metabolites, and cerebral small vessel disease: a mediation Mendelian Randomization study.

BACKGROUND: Sodium-glucose cotransporter 2 (SGLT2) and SGLT1 inhibitors may have additional beneficial metabolic effects on circulating metabolites beyond glucose regulation, which could contribute to a reduction in the burden of cerebral small vessel disease (CSVD). Accordingly, we used Mendelian Randomization (MR) to examine the role of circulating metabolites in mediating SGLT2 and SGLT1 inhibition in CSVD. METHODS: Genetic instruments for SGLT1/2 inhibition were identified as genetic variants, which were both associated with the expression of encoding genes of SGLT1/2 inhibitors and glycated hemoglobin A1c (HbA1c) level. A two-sample two-step MR was used to determine the causal effects of SGLT1/2 inhibition on CSVD manifestations and the mediating effects of 1400 circulating metabolites linking SGLT1/2 inhibition with CSVD manifestations. RESULTS: A lower risk of deep cerebral microbleeds (CMBs) and small vessel stroke (SVS) was linked to genetically predicted SGLT2 inhibition. Better white matter structure integrity was also achieved, as evidenced by decreased mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD), as well as lower deep (DWMH) and periventrivular white matter hyperintensity (PWMH) volume. Inhibiting SGLT2 could also lessen the incidence of severe enlarged perivascular spaces (EPVS) located at white matter, basal ganglia (BG) and hippocampus (HIP). SGLT1 inhibition could preserve white matter integrity, shown as decreased MD of white matter and DWMH volume. The effect of SGLT2 inhibition on SVS and MD of white matter through the concentration of 4-acetamidobutanoate and the cholesterol to oleoyl-linoleoyl-glycerol (18:1 to 18:2) ratio, with a mediated proportion of 30.3% and 35.5% of the total effect, respectively. CONCLUSIONS: SGLT2 and SGLT1 inhibition play protective roles in CSVD development. The SGLT2 inhibition could lower the risk of SVS and improve the integrity of white matter microstructure via modulating the level of 4-acetamidobutanoate and cholesterol metabolism. Further mechanistic and clinical studies research are needed to validate our findings.

The effects of immunomodulatory drugs on cerebral small vessel disease: A mediation Mendelian randomization analysis.

BACKGROUND: There are only a few recognized drug targets for cerebral small vessel disease (CSVD). Though inflammation is increasingly implicated in the development of CSVD, it remains unclear whether immunomodulation could become a therapeutic target. Accordingly, the Mendelian randomization (MR) method was used to assess the genetically proxied impacts of IL6 receptor (IL6R) inhibitor, IL1ß inhibitor, Tumor necrosis factor (TNF) inhibitor and ß-tubulin inhibitor on CSVD through. METHODS: Single nucleotide polymorphisms (SNPs) near the IL6R, IL1ß, TNFRSF1A and ß-tubulin genes were identified as genetic proxies for immunomodulatory drugs. These SNPs exhibited significant associations with serum C-reactive protein (CRP) levels in a large European genome-wide association study. The causal effects of immunomodulatory drugs on CSVD manifestations and the mediation influence of 731 peripheral blood immune phenotypes linking these drugs to CSVD manifestations were examined using a two-sample two-step MR approach. RESULTS: A total of 9, 18, 4 and 1 SNP were identified to proxy the effects of IL1ß inhibitor, IL6R inhibitor, TNF inhibitor and ß-tubulin inhibitor, respectively. MR analysis showed a significant causal relationship between IL1ß inhibition and reduced volume of periventricular white matter hyperintensity (PWMH). IL6R inhibition was associated with a reduced risk of small vessel stroke, decreased axial diffusivity and mean diffusivity. Genetically proxied TNF inhibition may decrease the occurrence of cerebral microbleeds (CMBs) and severe enlarged perivascular spaces located at white matter (WM-EPVS). It could also protect WM integrity, as evidenced by the reduced volumes of PWMH and deep white matter hyperintensity (DWMH). Various peripheral blood immune phenotypes exhibited significant associations with immunomodulatory drugs. Notably, the median fluorescence intensity (MFI) of CD45 on CD8br cells partially mediated the effects of IL1ß inhibitor on PWMH volume. Indirect effects of TNF inhibition on PWMH and DWMH volume through the MFI of CD127 on CD28- CD8br cells were observed. The effects of TNF inhibition on the occurrence of any CMBs were partially mediated by the MFI of CD45 on natural killer T cells, and the effects of TNF inhibition on the occurrence of lobar CMBs were partially mediated by the MFI of HLA DR on CD33- HLA DR+ cells. Furthermore, the MFI of HLA DR on CD33- HLA DR+ cells partially mediated the effects of TNF inhibition on WM-EPVS. CONCLUSIONS: IL1ß inhibitor, IL6R inhibitor and TNF inhibitor were associated with lower burden of CSVD while the activation of certain immune cells such as Tregs and myeloid cells partially mediated their protective effects.