Multiomics insight into the role of glucagon-like peptide-1 receptor agonists in heart failure

Cardiovascular diseases, such as atrial fibrillation, coronary artery disease, heart failure (HF) and ischaemic stroke, are leading causes of death globally and exert major global health burden. Recent studies suggest that glucagon-like peptide-1 receptor agonists (GLP1Ra), a novel class of antidiabetic drugs, may not only help manage blood glucose but also reduce the risks of cardiovascular diseases. However, the mechanisms through which GLP1Ra protects against cardiovascular diseases, remain incompletely understood.

Genome-wide association study dates were used to investigate the impact of GLP1Ra on cardiovascular diseases, including atrial fibrillation (1,202,168 European and 28,612 East Asian), coronary artery disease (501,756 European and 183,134 East Asian), heart failure (HF) (1,350,497 European and 203,040 East Asian) and ischaemic stroke (689,168 European and 192,383 East Asian). Genetic instruments were selected from the GLP1R gene region, and two-sample Mendelian randomization (MR) analyses were conducted to assess the causal effects of GLP1Ra on cardiovascular diseases in European and East Asian populations. Summary-data-based MR analyses were performed for further validation using expression quantitative trait loci data. Mediation analysis evaluates the role of circulating inflammatory proteins and metabolites in mediating the effects of GLP1Ra. Meantime, we performed a series of sensitivity analyses to confirm the robustness of the results. The result demonstrated significant causal association between GLP1Ra and HF in European populations (odds ratio: 0.60, 95% CI 0.51-0.72, P = 2.76 × 10^-8), and this result was confirmed by SMR analyses. No significant associations were found for atrial fibrillation, coronary artery disease, ischaemic stroke in European populations or all cardiovascular diseases in East Asian populations. GLP1Ra was found to influence 27 circulating inflammatory proteins and 146 circulating metabolites. Among them, 4 inflammatory proteins and 17 metabolites are associated with HF. Mediation analysis indicated that the protective effect of GLP1Ra on HF was mediated by circulating fibroblast growth factor 5 (FGF5) and N-acetylglycine (NAC), with a mediated proportion of 4.37% and 8% of the total effect, respectively.

This study provides multiomics insight into the role of GLP1Ra in cardiovascular diseases, especially in HF and the underlying pathway. The results suggest that GLP1Ra may exert anti-HF effects by reducing the concentration of circulating FGF5 and increasing the levels of circulating NAC, and enriches the potential mechanisms through which GLP1Ra alleviates HF.