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Sodium-glucose cotransporter 2 inhibitors, inflammation, and heart failure: a two-sample Mendelian randomization
Wenqin Guo1, Lingyue Zhao2, Weichao Huang1
1Fuwai Hospital Chinese Academy of Medical Sciences, Shenzhen, China.
Insights
Sodium-glucose cotransporter 2 (SGLT-2) inhibitors reduce heart failure (HF) risk, potentially via anti-inflammatory pathways. C-X-C motif chemokine ligand 10 (CXCL10) mediates this effect, suggesting a new therapeutic target for HF.
Area of Science:
- Cardiovascular Medicine
- Pharmacology
- Genetics
Background:
- Sodium-glucose cotransporter 2 (SGLT-2) inhibitors are recognized for improving heart failure (HF) outcomes.
- The precise mechanisms underlying SGLT-2 inhibitors' benefits in HF are not fully understood.
- Evidence suggests a role for anti-inflammatory pathways in mitigating HF risk.
Approach:
- A two-sample, two-step Mendelian Randomization (MR) approach was used to investigate the causal relationship between SGLT-2 inhibition and HF.
- Genetic variants linked to SGLT-2 inhibition and 92 inflammatory biomarkers were analyzed using large-scale genome-wide association study (GWAS) data.
- HF risk was assessed in relation to SGLT-2 inhibition and inflammatory biomarkers, including C-X-C motif chemokine ligand 10 (CXCL10).
Key Points:
- Genetically predicted SGLT-2 inhibition was significantly associated with a reduced risk of HF (OR 0.42).
- CXCL10 and leukemia inhibitory factor were identified as inflammatory biomarkers associated with both SGLT-2 inhibition and HF.
- Multivariable MR analysis indicated CXCL10 as a primary inflammatory mediator in HF, explaining 17.85% of the SGLT-2 inhibition's effect on HF risk.
Conclusions:
- This study provides genetic evidence for the anti-inflammatory effects of SGLT-2 inhibitors in reducing HF risk.
- CXCL10 is identified as a key mediator in the beneficial effects of SGLT-2 inhibitors on HF.
- Targeting CXCL10 may represent a novel therapeutic strategy for managing heart failure.
Background:
Sodium-glucose cotransporter 2 (SGLT-2) inhibitors are increasingly recognized for their role in reducing the risk and improving the prognosis of heart failure (HF). However, the precise mechanisms involved remain to be fully delineated. Evidence points to their potential anti-inflammatory pathway in mitigating the risk of HF.
Methods:
A two-sample, two-step Mendelian Randomization (MR) approach was employed to assess the correlation between SGLT-2 inhibition and HF, along with the mediating effects of inflammatory biomarkers in this relationship. MR is an analytical methodology that leverages single nucleotide polymorphisms as instrumental variables to infer potential causal inferences between exposures and outcomes within observational data frameworks. Genetic variants correlated with the expression of the SLC5A2 gene and glycated hemoglobin levels (HbA1c) were selected using datasets from the Genotype-Tissue Expression project and the eQTLGen consortium. The Genome-wide association study (GWAS) data for 92 inflammatory biomarkers were obtained from two datasets, which included 14,824 and 575,531 individuals of European ancestry, respectively. GWAS data for HF was derived from a meta-analysis that combined 26 cohorts, including 47,309 HF cases and 930,014 controls. Odds ratios (ORs) and 95% confidence interval (CI) for HF were calculated per 1 unit change of HbA1c.
Results:
Genetically predicted SGLT-2 inhibition was associated with a reduced risk of HF (OR 0.42 [95% CI 0.30-0.59], P < 0.0001). Of the 92 inflammatory biomarkers studied, two inflammatory biomarkers (C-X-C motif chemokine ligand 10 [CXCL10] and leukemia inhibitory factor) were associated with both SGLT-2 inhibition and HF. Multivariable MR analysis revealed that CXCL10 was the primary inflammatory cytokine related to HF (MIP = 0.861, MACE = 0.224, FDR-adjusted P = 0.0844). The effect of SGLT-2 inhibition on HF was mediated by CXCL10 by 17.85% of the total effect (95% CI [3.03%-32.68%], P = 0.0183).
Conclusions:
This study provides genetic evidence supporting the anti-inflammatory effects of SGLT-2 inhibitors and their beneficial impact in reducing the risk of HF. CXCL10 emerged as a potential mediator, offering a novel intervention pathway for HF treatment.
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