SGLT1 and SGLT2 inhibition, circulating metabolites, and cerebral small vessel disease: a mediation Mendelian Randomization study
Authors' conclusion
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.
Study context
- Population
- Genetic data on cerebral small vessel disease (CSVD) manifestations and 1400 circulating metabolites
- Comparison
- Genetically predicted SGLT2 and SGLT1 inhibition
- Outcome
- Causal effects of SGLT1/2 inhibition on CSVD manifestations and mediating effects of circulating metabolites
Methodological detailstwo-sample two-step Mendelian Randomization (MR), mediation analysis
- Two-sample two-step MR
- Mediation analysis
Main finding
As reported in the abstract
CSVD manifestations
- SGLT2 inhibition linked to lower risk of deep cerebral microbleeds and small vessel stroke (SVS)
- SGLT2 inhibition: decreased white matter mean diffusivity, axial diffusivity and radial diffusivity; lower deep and periventricular white matter hyperintensity volume
- SGLT2 inhibition: lower incidence of severe enlarged perivascular spaces in white matter, basal ganglia and hippocampus
- SGLT1 inhibition: decreased white matter mean diffusivity and deep white matter hyperintensity volume
Further findings
Mediation by circulating metabolites
- Mediated proportion of SGLT2 inhibition effect on SVS via 4-acetamidobutanoate
- 30.3%
- Mediated proportion of SGLT2 inhibition effect on white matter mean diffusivity via cholesterol to oleoyl-linoleoyl-glycerol (18:1 to 18:2) ratio
- 35.5%
Original publication
SGLT1 and SGLT2 inhibition, circulating metabolites, and cerebral small vessel disease: a mediation Mendelian Randomization study. Cardiovasc Diabetol. Published 7 May 2024. doi:10.
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