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SGLT2 inhibition, blood lipids, and cardiovascular disease: A Mendelian randomization study
Jiangtao Li1,2,3, Chenhe Li1,2,3, Xin Feng1,2,3
1Division of Cardiovascular Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Aims:
We aim to investigate the causal effect of blood lipids mediating sodium-glucose cotransporter 2 (SGLT2) inhibition in cardiovascular disease (CVD) using Mendelian randomization (MR).
Methods And Results:
A two-sample two-step MR study was conducted to evaluate the association of SGLT2 inhibition with CVDs and the mediation effects of blood lipids linking SGLT2 inhibition with CVDs. Genetic instruments for SGLT2 inhibition were identified as genetic variants, which were associated with the expression of the SLC5A2 gene and glycated haemoglobin level (HbA1c). SGLT2 inhibition was associated with reduced risk of heart failure (HF) (OR 0.44 [95% CI 0.32-0.61]; P = 6.0 × 10-7), atrial fibrillation (AF) (0.47 [0.37-0.61]; P = 1.81 × 10-8), coronary artery disease (CAD) (0.47 [0.30-0.73]; P = 7.46 × 10-4), myocardial infarction (MI) (0.30 [0.15-0.61]; P = 7.44 × 10-4), any stroke (AS) (0.28 [0.18-0.42]; P = 1.14 × 10-9), and ischaemic stroke (IS) (0.27 [0.17-0.44]; P = 1.97 × 10-7). Our results indicated that the proportion mediated of the mediating effect of total cholesterol was 1.7% (OR 0.99 [95% CI 0.98, 0.99], P = 0.004), 4.7% (0.96 [0.95, 0.98], P = 0.002), and 2.7% (0.97 [0.95, 0.98], P = 0.002) in the association between SGLT2 inhibition and the risk of HF, CAD, and MI, respectively. For low-density lipoprotein cholesterol, the proportion mediated of the mediating effect was 2.2% for HF (OR 0.98 [95% CI 0.98, 0.99], P = 0.003), 8.6% for CAD (0.93 [0.91, 0.95], P = 5.74 × 10-4), and 5.0% for MI (0.95 [0.94, 0.96], P = 6.97 × 10-4). For non-high-density lipoprotein cholesterol, the proportion mediated of the mediating effect was 3.4% for HF (OR 0.98 [95% CI 0.97, 0.98], P = 4.42 × 10-6), 11.8% for CAD (0.92 [0.90, 0.93], P = 7.23 × 10-8), 5.7% for MI (0.94 [0.92, 0.95], P = 8.17 × 10-7), 1.5% for AS (0.98 [0.98, 0.99], P = 0.001), and 1.4% for IS (0.98 [0.98, 0.99], P = 0.004).
Conclusions:
Our study showed the association of SGLT2 inhibition with the reduced risk of CVDs and blood lipids might mediate this association.
Insights
Sodium-glucose cotransporter 2 (SGLT2) inhibition reduces cardiovascular disease (CVD) risk, with blood lipids partially mediating this protective effect. This Mendelian randomization study highlights lipid pathways in SGLT2 inhibitor benefits.
Area of Science:
- Cardiovascular Medicine
- Pharmacogenomics
- Metabolic Research
Background:
- Sodium-glucose cotransporter 2 (SGLT2) inhibitors are increasingly used for managing type 2 diabetes and heart failure.
- The cardiovascular benefits of SGLT2 inhibition are well-established, but the underlying mechanisms, particularly the role of blood lipids, require further elucidation.
Purpose of the Study:
- To investigate the causal effect of blood lipids in mediating the association between SGLT2 inhibition and cardiovascular disease (CVD) risk.
- To quantify the proportion of the SGLT2 inhibition-associated CVD risk reduction mediated by specific lipid fractions.
Main Methods:
- A two-sample, two-step Mendelian randomization (MR) study was employed.
- Genetic variants associated with SGLT2 inhibition (via SLC5A2 gene expression and HbA1c) were used as instrumental variables.
- The mediation effects of total cholesterol, LDL-C, and non-HDL-C on the association between SGLT2 inhibition and CVD outcomes (HF, CAD, MI, AS, IS) were assessed.
Main Results:
- SGLT2 inhibition was significantly associated with a reduced risk of heart failure (HF), coronary artery disease (CAD), myocardial infarction (MI), any stroke (AS), and ischaemic stroke (IS).
- Blood lipids, including total cholesterol, LDL-C, and non-HDL-C, were found to partially mediate the protective effects of SGLT2 inhibition against specific CVDs.
- Non-high-density lipoprotein cholesterol showed the largest mediation proportion for CAD (11.8%), MI (5.7%), and HF (3.4%).
Conclusions:
- SGLT2 inhibition confers significant protection against major cardiovascular diseases.
- Blood lipids, particularly non-HDL-C, play a measurable role in mediating the cardiovascular benefits of SGLT2 inhibitors.
- These findings reinforce the importance of lipid management in patients treated with SGLT2 inhibitors.
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