钠-葡萄糖协同转运蛋白2抑制剂、血脂与心血管疾病：一项孟德尔随机化研究

SGLT2 inhibition, blood lipids, and cardiovascular disease: A Mendelian randomization study.

作者信息

Li Jiangtao, Li Chenhe, Feng Xin, Wei Xiang

机构信息

Division of Cardiovascular Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, China.

出版信息

ESC Heart Fail. 2024 Dec;11(6):3960-3971. doi: 10.1002/ehf2.14987. Epub 2024 Jul 25.

DOI:10.1002/ehf2.14987

PMID:39054757

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11631244/

Abstract

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), atrial fibrillation (AF) (0.47 [0.37-0.61]; P = 1.81 × 10), coronary artery disease (CAD) (0.47 [0.30-0.73]; P = 7.46 × 10), myocardial infarction (MI) (0.30 [0.15-0.61]; P = 7.44 × 10), any stroke (AS) (0.28 [0.18-0.42]; P = 1.14 × 10), and ischaemic stroke (IS) (0.27 [0.17-0.44]; P = 1.97 × 10). 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), and 5.0% for MI (0.95 [0.94, 0.96], P = 6.97 × 10). 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), 11.8% for CAD (0.92 [0.90, 0.93], P = 7.23 × 10), 5.7% for MI (0.94 [0.92, 0.95], P = 8.17 × 10), 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.

摘要

目的

我们旨在利用孟德尔随机化（MR）研究血脂在介导钠-葡萄糖协同转运蛋白2（SGLT2）抑制与心血管疾病（CVD）之间因果关系中的作用。

方法与结果

进行了一项两样本两步MR研究，以评估SGLT2抑制与心血管疾病的关联，以及血脂在连接SGLT2抑制与心血管疾病中的中介作用。将与SLC5A2基因表达和糖化血红蛋白水平（HbA1c）相关的基因变异鉴定为SGLT2抑制的遗传工具。SGLT2抑制与心力衰竭（HF）风险降低相关（OR 0.44 [95% CI 0.32 - 0.61]；P = 6.0×10）、心房颤动（AF）（0.47 [0.37 - 0.61]；P = 1.81×10）、冠状动脉疾病（CAD）（0.47 [0.30 - 0.73]；P = 7.46×10）、心肌梗死（MI）（0.30 [0.15 - 0.61]；P = 7.44×10）、任何卒中（AS）（0.28 [0.18 - 0.42]；P = 1.14×10）和缺血性卒中（IS）（0.27 [0.17 -

0.44]；P = 1.97×10）。我们的结果表明，在SGLT2抑制与HF、CAD和MI风险的关联中，总胆固醇中介效应的介导比例分别为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）和2.7%（0.97 [0.9, 0.98]，P = 0.002）。对于低密度脂蛋白胆固醇，在HF中的介导比例为2.2%（OR 0.98 [95% CI 0.98, 0.99]，P = 0.003），在CAD中为8.6%（0.93 [0.91, 0.95]，P = 5.74×10），在MI中为5.0%（0.95 [0.94, 0.96]，P = 6.97×10）。对于非高密度脂蛋白胆固醇，在HF中的介导比例为3.4%（OR 0.98 [95% CI 0.97, 0.98]，P = 4.42×10），在CAD中为11.8%（0.92 [0.90, 0.93]，P = 7.23×10），在MI中为5.7%（0.94 [0.92, 0.95]，P = 8.17×10），在AS中为1.5%（0.98 [0.98, 0.99]，P = 0.001），在IS中为1.4%（0.98 [0.98, 0.99]，P = 0.004）。