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Updated: Jun 25, 2025
Mouse Complete Stasis Model of Inferior Vena Cava Thrombosis
Published on: June 15, 2011
SGLT2 inhibition, venous thrombolism, and death due to cardiac causes: a mediation Mendelian randomization study
Lili Shi1,2, Xiupan Wei3, Jinlan Luo1,2
1Department of Geriatric Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Objective:
To investigate the causal role of venous thrombolism mediating sodium-glucose cotransporter 2 (SGLT2) inhibition in death due to cardiac causes using Mendelian randomization (MR).
Methods:
A two-sample two-step MR was used to determine (1) the causal effects of SGLT2 inhibition on death due to cardiac causes; (2) the causal effects of venous thrombolism on death due to cardiac causes; and (3) the mediation effects of venous thrombolism. Genetic proxies for SGLT2 inhibition were identified as variants in the SLC5A2 gene that were associated with both levels of gene expression and hemoglobin A1c. Additionally, employing MR to investigate the causal association between SGLT2 inhibition and cardiac arrest as well as coronary heart disease (CHD).
Results:
SGLT2 inhibition was associated with a lower risk of death due to cardiac causes (odds ratio [OR] = 0.983, [95% CI = 0.972, 0.993], P = 0.0016). Venous thrombolism was associated with death due to cardiac causes ([OR] = 1.031, [95% CI = 1.005, 1.057], P = 0.0199). Mediation analysis showed evidence of indirect effect of SGLT2 inhibition on death due to cardiac causes through venous thrombolism [β = -0.0015, (95% CI = -0.0032 -0.0002), P = 0.042], with a mediated proportion of 8.9% (95% CI = 1.2%, 18.7%) of the total. Furthermore, SGLT2 inhibition was linked to a lower risk of cardiac arrest ([OR] = 0.097, [95% CI = 0.013, 0.742], P = 0.025). SGLT2 inhibition was linked to a lower risk of CHD ([OR] = 0.957, [95% CI = 0.932, 0.982], P = 0.0009).
Conclusions:
Our study identified the causal roles of SGLT2 inhibition in venous thrombolism. SGLT2 inhibition may influence death due to cardiac causes through venous thrombolism. Additionally, SGLT2 inhibition was associated with reduced risk of cardiac arrest and CHD.
Insights
Sodium-glucose cotransporter 2 (SGLT2) inhibition may reduce cardiac death risk by affecting venous embolism. This study used Mendelian randomization to explore the causal link between SGLT2 inhibition, venous embolism, and cardiac death.
Area of Science:
- Cardiovascular Medicine
- Pharmacogenomics
- Thrombosis Research
Background:
- Sodium-glucose cotransporter 2 (SGLT2) inhibitors are increasingly used for managing type 2 diabetes and heart failure.
- The precise mechanisms by which SGLT2 inhibitors exert their cardiovascular benefits are still under investigation.
- Venous thromboembolism (VTE) is a significant complication with potential links to cardiovascular outcomes.
Purpose of the Study:
- To investigate the potential mediating role of venous thromboembolism (VTE) in the relationship between SGLT2 inhibition and cardiac death.
- To establish the causal effects of SGLT2 inhibition and VTE on cardiac mortality using Mendelian randomization (MR).
- To explore the association between SGLT2 inhibition and other cardiovascular events like cardiac arrest and coronary heart disease (CHD).
Main Methods:
- A two-sample, two-step Mendelian randomization (MR) design was employed.
- Genetic variants in the SLC5A2 gene served as instrumental variables for SGLT2 inhibition.
- MR was used to assess the causal effect of SGLT2 inhibition on cardiac death, VTE on cardiac death, and the indirect effect of SGLT2 inhibition on cardiac death via VTE.
Main Results:
- SGLT2 inhibition was associated with a reduced risk of cardiac death (OR=0.983, P=0.0016).
- Venous thromboembolism showed an association with increased cardiac death risk (OR=1.031, P=0.0199).
- Mediation analysis indicated an indirect effect of SGLT2 inhibition on cardiac death through VTE (β=-0.0015, P=0.042), accounting for 8.9% of the total effect. SGLT2 inhibition also reduced the risk of cardiac arrest and CHD.
Conclusions:
- SGLT2 inhibition appears to causally influence venous thromboembolism, which in turn may mediate its effect on reducing cardiac death.
- These findings suggest a novel pathway for the cardiovascular benefits of SGLT2 inhibitors.
- SGLT2 inhibition is associated with a lower risk of cardiac arrest and coronary heart disease.
