GLP-1R agonists and heart failure: novel beneficial effects suggested by Mendelian randomization

孟德尔随机化 医学 还原(数学) 随机化 内科学 糖尿病 药理学 兴奋剂 生物信息学 受体 心力衰竭 2型糖尿病 心脏病学 剩余风险 心肌梗塞 随机对照试验 梅德林 二羟基化合物 内分泌学 临床试验
作者
Yiqing Hu,Yongchao Zhao,Neng Li Dai,You Zhou,Yunqian Yao,Z. Li,Wufeng Cai,Weidong Xiong,Shuai Song,Xin Deng,Jiasheng Yin,Xin Zhao,Xinyu Weng,Chenguang Li,Aijun Sun,Juying Qian,Hao Lu,Junbo Ge
出处
期刊:European Heart Journal [Oxford University Press]
卷期号:47 (19): 2308-2322 被引量:6
标识
DOI:10.1093/eurheartj/ehaf1066
摘要

BACKGROUND AND AIMS: Glucagon-like peptide-1 receptor agonists reduce heart failure (HF) risk in patients with diabetes or obesity. However, the extent to which this reduced risk is dependent on, or extends beyond, glucose control and weight reduction remains unclear. METHODS: Two-sample cis-Mendelian randomization (MR) was used to assess causal effects of GLP-1R activation on HF risk, using glycated haemoglobin (HbA1c) reduction as a surrogate biomarker. The HF outcome was derived from a genome-wide association meta-analysis that included seven original studies and 1 665 481 participants. Primary analyses used inverse variance-weighted (IVW) and MR-robust adjusted profile score (MR-RAPS) methods. Mendelian randomization Bayesian model averaging was used to identify key mediators of the observed effects, while multivariable cis-MR with principal component generalized method of moments and network cis-MR were used to minimize the impact of confounders. RESULTS: Genetically proxied GLP-1R activation was associated with reduced HF risk {IVW: odds ratio [OR] [95% confidence interval (CI)] .502 [.339, .743]; MR-RAPS: OR [95% CI] .492 [.320, .756]}. Mendelian randomization Bayesian model averaging identified body mass index (BMI) (marginal inclusion probability 67.2%) and Type 2 diabetes (T2D) (45.0%) as primary mediators. In multivariable cis-MR with principal component generalized method of moments, genetically predicted HbA1c levels from the GLP-1R locus remained significantly associated with HF risk after BMI adjustment, even in instances where BMI effects were non-significant [OR (95% CI) 1.663 (1.087, 2.544) at 99% variance threshold]. Network cis-MR confirmed persistent protection after adjusting for BMI [IVW: OR (95% CI) .587 (.394, .877); MR-RAPS: OR (95% CI) .577 (.375, .887)] or T2D [IVW: OR (95% CI) .508 (.343, .754); MR-RAPS: OR (95% CI) .499 (.327, .762)]. CONCLUSIONS: Glucagon-like peptide-1 receptor agonist-associated HF risk reduction is primarily mediated by BMI reduction rather than glucose control, but not fully explained by either. Residual effects after BMI and T2D adjustment suggest direct cardioprotective actions, supporting trials in non-obese, non-diabetic HF patients.
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