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Updated: Jun 14, 2025
Author Spotlight: Exploring the Relationship Between Lipotoxicity and HFpEF
Published on: March 29, 2024
Causal relationships between GLP1 receptor agonists, blood lipids, and heart failure: a drug-target mendelian
Tianshi Mao1, Jie Chen2, Tong Su3
1Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100700, China.
Background:
Glucagon-like peptide-1 receptor (GLP1R) agonists have been shown to reduce major cardiovascular events in diabetic patients, but their role in heart failure (HF) remains controversial. Recent evidence implies their potential benefits on cardiometabolism such as lipid metabolism, which may contribute to lowering the risk of HF. Consequently, we designed a Mendelian randomization (MR) study to investigate the causal relationships of circulating lipids mediating GLP1R agonists in HF.
Methods:
The available cis-eQTLs for GLP1R target gene were selected as instrumental variables (IVs) of GLP1R agonism. Positive control analyses of type 2 diabetes mellitus (T2DM) and body mass index (BMI) were conducted to validate the enrolled IVs. Two-sample MR was performed to evaluate the associations between GLP1R agonism and HF as well as left ventricular ejection fraction (LVEF). Summary data for HF and LVEF were obtained from two genome-wide association studies (GWASs), which included 977,323 and 40,000 individuals of European ancestry, respectively. The primary method employed was the random-effects inverse variance weighted, with several other methods used for sensitivity analyses, including MR-Egger, MR PRESSO, and weighted median. Additionally, multivariable MR and mediation MR were applied to identify potentially causal lipid as mediator.
Results:
A total of 18 independent IVs were included. The positive control analyses showed that GLP1R agonism significantly reduced the risk of T2DM (OR = 0.79, 95% CI = 0.75-0.85, p < 0.0001) and decreased BMI (OR = 0.95, 95% CI = 0.93-0.96, p < 0.0001), ensuring the effectiveness of selected IVs. We found favorable evidence to support the protective effect of GLP1R agonism on HF (OR = 0.75, 95% CI = 0.71-0.79, p < 0.0001), but there was no obvious correlation with increased LVEF (OR = 1.01, 95% CI = 0.95-1.06, p = 0.8332). Among the six blood lipids, only low-density lipoprotein cholesterol (LDL-C) was both associated with GLP1R agonism and HF. The causal effect of GLP1R agonism on HF was partially mediated through LDL-C by 4.23% of the total effect (95% CI = 1.04-7.42%, p = 0.0093).
Conclusions:
This study supported the causal relationships of GLP1R agonists with a reduced risk of HF. LDL-C might be the mediator in this association, highlighting the cardiometabolic benefit of GLP1R agonists on HF.
Insights
Glucagon-like peptide-1 receptor (GLP1R) agonists show a protective effect against heart failure (HF). Low-density lipoprotein cholesterol (LDL-C) may mediate this benefit, underscoring the cardiometabolic advantages of GLP1R agonists in HF patients.
Area of Science:
- Cardiovascular Research
- Metabolic Disease Research
- Pharmacogenomics
Background:
- Glucagon-like peptide-1 receptor (GLP1R) agonists are known to reduce cardiovascular events in diabetic patients.
- Their specific role in heart failure (HF) remains under investigation, though potential benefits via cardiometabolism and lipid regulation are suggested.
Purpose of the Study:
- To investigate the causal relationships between GLP1R agonism, circulating lipids, and heart failure (HF) using a Mendelian randomization (MR) approach.
- To identify potential lipid mediators in the association between GLP1R agonists and HF risk.
Main Methods:
- Utilized cis-eQTLs for the GLP1R target gene as instrumental variables for GLP1R agonism.
- Performed two-sample MR analyses using large genome-wide association study (GWAS) data for HF and left ventricular ejection fraction (LVEF).
- Employed inverse variance weighted, MR-Egger, MR PRESSO, and weighted median methods for primary and sensitivity analyses; multivariable and mediation MR were used to identify lipid mediators.
Main Results:
- Validated instrumental variables by confirming GLP1R agonism's significant reduction in type 2 diabetes mellitus (T2DM) risk and body mass index (BMI).
- Found significant evidence supporting a protective effect of GLP1R agonism on HF risk (OR=0.75, P<0.0001), with no significant association with LVEF.
- Identified low-density lipoprotein cholesterol (LDL-C) as the only significantly associated lipid, mediating 4.23% of the total effect of GLP1R agonism on HF.
Conclusions:
- This MR study provides causal evidence that GLP1R agonists reduce the risk of heart failure.
- Low-density lipoprotein cholesterol (LDL-C) is identified as a potential mediator, highlighting the cardiometabolic benefits of GLP1R agonists in the context of HF.
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