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SGLT2 inhibition, high-density lipoprotein, and kidney function: a mendelian randomization study.
Zhijuan Wang1,2, Jie Wei1,2, Wenman Zhao1,2
1Department of Nephrology, the Second Affiliated Hospital of Anhui Medical University, 678 Furong Road, Hefei, 230601, Anhui, China.
Lipids in Health and Disease
|March 21, 2024
Summary
Sodium-glucose cotransporter 2 (SGLT2) inhibition benefits kidney function by increasing high-density lipoprotein (HDL) particle concentrations. This study reveals HDL mediates SGLT2 inhibition
Area of Science:
- Nephrology
- Metabolomics
- Genetics
Background:
- Sodium-glucose cotransporter 2 (SGLT2) inhibition shows renoprotective effects in diabetic kidney disease.
- Emerging data suggest SGLT2 inhibition benefits kidney function irrespective of diabetes status, but mechanisms are unclear.
- This study investigates the role of circulating metabolites in SGLT2 inhibition's renal effects.
Purpose of the Study:
- To examine the influence of circulating metabolites on SGLT2 inhibition's impact on kidney function using Mendelian randomization (MR).
- To identify specific metabolites that mediate the renoprotective effects of SGLT2 inhibition.
Main Methods:
- Employed a Mendelian randomization (MR) approach utilizing genetic proxies for SGLT2 inhibition.
- Analyzed summary statistics from genome-wide association studies (GWAS) for kidney function parameters (eGFR, UACR, albuminuria).
- Integrated blood metabolite data from 249 biomarkers in the UK Biobank and performed two-step MR to identify mediating metabolites.
Main Results:
- Genetically predicted SGLT2 inhibition was associated with reduced type 2 diabetes mellitus risk (OR=0.55).
- SGLT2 inhibition positively impacted estimated glomerular filtration rate (eGFR) (β=0.05) and reduced urine albumin-to-creatinine ratio (UACR) and albuminuria.
- Small high-density lipoprotein (HDL) particle concentration was identified as a key mediator, explaining 13.33% of the renal function improvement (β=0.01).
Conclusions:
- This study provides genetic evidence linking SGLT2 inhibition, circulating metabolites, and renal function.
- High-density lipoprotein (HDL) particle concentration significantly mediates the renoprotective effects of SGLT2 inhibition.
- Findings enhance understanding of SGLT2 inhibition mechanisms and support its role in renal function preservation.
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