The potential of glucagon-like peptide-1 receptor agonists in heart failure

Abstract

Heart failure (HF) remains one of the cardiovascular diseases (CVDs) associated with a high unmet medical need due to high morbidity and mortality rates and lack of efficacious interventions. HF is closely related to cardiometabolic diseases such as diabetes, obesity and chronic kidney disease, and strategies that address most or all these intertwined conditions are desirable. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are approved for type 2 diabetes (T2D), and some are also indicated for reduction of the risk of atherosclerotic CVD in T2D and for weight management. As we summarise in this concise review, preliminary evidence suggests that the cardioprotective benefits of GLP-1 RAs may also extend to HF. The most robust clinical evidence arguably originates from the large cardiovascular outcomes trials (CVOTs) completed for most GLP-1 RAs, of which the latest showed a significant relative risk reduction (RRR) of 39% (HR) with once-weekly efpeglenatide on HF requiring hospitalisation, corroborating a meta-analysis which found a significant RRR across eight GLP-1 RA CVOTs of 11%. Further, although incompletely described, multiple studies are available to provide insights into the mechanistic underpinnings, which appear to be associated mostly with indirect cardioprotective benefits owing to the ability of GLP-1 RAs to address hyperglycaemia, and reduce body weight, and, amongst others, inflammation. In sum, current evidence positions GLP-1 RAs as a potential cardioprotective strategy in HF, with HF with preserved ejection fraction emerging as the clinically most relevant phenotype for the drug class, especially when occurring in people with obesity with and without diabetes.

Evidence that tirzepatide protects against diabetes-related cardiac damages

“…Moreover, the expression of GLP-1R in the human atria, ventricles, and cardiomyocytes suggests a potential direct action of GLP-1RAs on the heart and indicates that the human receptor is expressed in the sinoatrial node [ 10 ]. This is in line with the chronotropic effects of GLP-1RAs treatment, which, in a large meta-analysis, was shown to be associated with heart rate increases of up to 3.35 beats/min [ 8 , 11 ]. Apart from the chronotropic effects, the direct effects of GLP-1, specifically on the heart, have not been comprehensively documented.…”

“…However, unlike sodium-glucose co-transporter 2 (SGLT2) inhibitors [ 7 ], evidence of a benefit for GLP-1 RAs in heart failure (HF) is controversial and remains to be fully established in dedicated studies [ 8 ].…”

Targeting G protein‐coupled receptors for heart failure treatment

“…GLP-1 agonists, including exenatide, liraglutide, semaglutide and dulaglutide, have been assessed for decreasing cardiovascular events in diabetic patients (Cosentino et al, 2020;Kreiner et al, 2022). In the LEADER trial, liraglutide significantly reduced cardiovascular and allcause deaths at 3.1 years in patients with type 2 diabetes and high cardiovascular risk (Marso et al, 2016).…”

“…The extended half‐lives of GLP‐1 agonists may contribute to their beneficial cardiovascular effects (McDonagh et al, 2021). Current studies suggest GLP‐1 agonists predominantly confer cardiovascular benefit by decreasing atherosclerosis‐related events (Kreiner et al, 2022). However, different GLP‐1 agonists can have distinct activation profiles (Zhang et al, 2020) and as such, the influence of different GLP‐1 agonists in the treatment of heart failure deserves further exploration.…”

Role of Glucagon-Like Peptide-1 (GLP-1) Receptor Agonists in Cardiovascular Risk Management in Patients With Type 2 Diabetes Mellitus: A Systematic Review

“…Even though the CVOTs frequently featured a significant count of people with T2D and HF at enrollment, it must be highlighted that the majority of the CVOTs did not analyze outcomes based on the presence of HF at enrollment. Additionally, the studies' definitions of HF varied and were generally vague [ 29 ].…”