SGLT2 inhibition mitigates intracerebral hemorrhage risk by modulating inflammation

Mingsheng Huang; Yiheng Liu; Cheng Chen

doi:10.1038/s41598-024-84118-4

SGLT2 inhibition mitigates intracerebral hemorrhage risk by modulating inflammation

Sci Rep. 2025 May 22;15(1):17770. doi: 10.1038/s41598-024-84118-4.

Authors

Mingsheng Huang¹, Yiheng Liu², Cheng Chen³

Affiliations

¹ Department of Neurosurgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
² Department of Cardiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
³ Department of Intensive Care Unit, JianYang Hospital of Traditional Chinese Medicine, 421 Xiongzhou Avenue South Section, Jianyang, 641499, Sichuan Province, China. chengchen202405@163.com.

Abstract

Sodium-glucose cotransporter 2 (SGLT-2) inhibitors have been increasingly recognized for their potential neuroprotective properties. Nevertheless, their effects on intracerebral hemorrhage (ICH) are still debated, with the precise mechanisms involved remaining unclear. Recent studies indicate that these inhibitors might lower ICH risk through anti-inflammatory mechanisms. This study analyzed genome-wide association study (GWAS) data from individuals of European ancestry, focusing on the relationship between 92 inflammatory biomarkers and ICH. A two-sample, two-step Mendelian randomization (MR) approach was used to examine the potential connection between SGLT-2 inhibition and ICH, as well as to investigate whether inflammatory biomarkers mediate this relationship. Genetic proxies for SGLT-2 inhibition were determined based on variants linked to the expression of the SLC5A2 gene and levels of glycated hemoglobin (HbA1c). Odds ratios with 95% confidence intervals were calculated to assess the associations between SGLT-2 inhibition, inflammatory biomarkers, and the likelihood of ICH. The genetic prediction of SGLT-2 inhibition was found to be inversely related to the risk of ICH (OR = 0.152; 95% CI = 0.066-0.352; P < 0.001). Out of the 92 inflammatory biomarkers examined, 33 showed a significant association with SGLT-2 inhibition. Notably, levels of IL10 receptor subunit beta (IL10RB) were significantly correlated with both SGLT-2 inhibition and ICH. Moreover, IL10RB accounted for 9.167% of the total mediation effect of SGLT-2 inhibition on ICH. The findings of this study suggest a link between SGLT-2 inhibition and a decreased risk of ICH, with IL10RB emerging as a possible mediator. This presents a potential new strategy for ICH prevention and intervention. Further studies are needed to clarify the role of inflammatory pathways in the connection between SGLT-2 inhibition and ICH.

Keywords: Causal effect; Inflammatory biomarkers; Intracerebral hemorrhage; Mendelian randomization; SGLT-2 inhibitors.

MeSH terms

Biomarkers
Cerebral Hemorrhage* / drug therapy
Cerebral Hemorrhage* / genetics
Cerebral Hemorrhage* / prevention & control
Female
Genome-Wide Association Study
Glycated Hemoglobin / metabolism
Humans
Inflammation* / drug therapy
Inflammation* / genetics
Male
Mendelian Randomization Analysis
Middle Aged
Polymorphism, Single Nucleotide
Risk Factors
Sodium-Glucose Transporter 2 Inhibitors* / pharmacology
Sodium-Glucose Transporter 2 Inhibitors* / therapeutic use
Sodium-Glucose Transporter 2* / genetics
Sodium-Glucose Transporter 2* / metabolism

Substances

Sodium-Glucose Transporter 2 Inhibitors
Sodium-Glucose Transporter 2
Biomarkers
SLC5A2 protein, human
Glycated Hemoglobin