The Role of GLP-1R and GIPR Agonism in Heart Failure

Heart failure (HF) is a clinical syndrome characterized by signs and symptoms of structural and functional cardiac abnormalities. It is corroborated by elevated N-terminal pro‑B‑type natriuretic peptide (NT-proBNP) levels and objective evidence of pulmonary or systemic congestion. More than 100,000 Canadians are diagnosed with HF annually. For years, HF has been classified based on left ventricular ejection fraction (LVEF). HF with reduced ejection fraction (HFrEF) refers to symptomatic HF with an LVEF <40%. However, if the LVEF is >50%, this is known as HF with preserved ejection fraction (HFpEF). In HFpEF, obesity is commonly implicated in the disease pathophysiology, and is present in up to 80% of people with this condition. Obesity contributes to concentric heart remodelling through mechanisms such as insulin resistance, diabetes, hyperlipidemia, visceral adipose tissue expansion, and myocardial steatosis. Additionally, obesity leads to a pro-inflammatory state which affects the vasculature and visceral organs.2 Glucagon‑like peptide-1 receptor agonists (GLP‑1RAs), such as semaglutide, have shown promise in weight reduction across multiple Phase 3 clinical trials. Agents combining GLP-1RA and glucose-dependent insulinotropic peptide receptor (GIPR) agonism, such as tirzepatide, have also contributed to clinically significant weight loss. As such, their impact in addressing obesity‑related HFpEF is under investigation. This paper reviews the data on GLP-1RAs and tirzepatide in patients with HF across the LVEF spectrum, with a particular focus on those with HFpEF.