GLP-1-based medications show emerging therapeutic potential for heart failure with preserved or mildly reduced ejection fraction

Heart failure with preserved ejection fraction (HFpEF) and mildly reduced ejection fraction (HFmrEF) represent significant clinical challenges, often characterized by complex metabolic dysfunction, inflammation, and obesity. Current therapeutic strategies are limited, leaving a substantial unmet need for effective treatments that address the multifaceted pathophysiology of these conditions. Glucagon-like Peptide 1 (GLP-1) receptor agonists, initially developed for type 2 diabetes mellitus (T2DM) and obesity, have demonstrated broad cardiovascular benefits, prompting investigation into their potential role in managing HFpEF and HFmrEF by targeting underlying metabolic and inflammatory pathways.

This comprehensive review systematically synthesizes current evidence on GLP-1-based medications for heart failure with preserved or mildly reduced ejection fraction (HFpEF/HFmrEF). It examines the established mechanisms of action for traditional GLP-1 receptor agonists and explores the therapeutic potential of newer dual and triple incretin agonists. The review focuses on how these agents, including tirzepatide (GLP-1/GIP), survodutide (GLP-1/GCG), mazdutide (GLP-1/GCG), and retatrutide (GLP-1/GIP/GCG), might impact the specific pathophysiological drivers of HFpEF and HFmrEF, drawing from preclinical and clinical data.

The review highlights that GLP-1 receptor agonists (GLP-1 RAs) are increasingly recognized for their therapeutic potential in heart failure, particularly in HFpEF and HFmrEF, extending beyond their established roles in type 2 diabetes mellitus (T2DM) and obesity. Their mechanisms of action encompass not only improved glycemic control but also direct and indirect cardiovascular benefits, such as weight loss, reduced inflammation, and improved endothelial function, which are highly relevant to the complex pathophysiology of these heart failure subtypes. The synthesis of evidence suggests that GLP-1 RAs contribute to improved metabolic profiles, which indirectly alleviate cardiac strain and improve cardiac function in susceptible populations.

The review emphasizes that novel dual and triple incretin agonists offer synergistic effects, potentially enhancing therapeutic outcomes in HFpEF/HFmrEF.

For instance, GIP co-agonism with GLP-1, as seen with tirzepatide, enhances the incretin effect and may counteract potential diabetogenic impacts of glucagon agonism. Chronic glucagon receptor agonism, exemplified by survodutide and mazdutide, is noted for its ability to increase energy expenditure and promote weight loss, crucial factors in improving outcomes for patients with HFpEF often complicated by obesity. The emerging triple agonists like retatrutide are positioned to offer even broader metabolic and cardiovascular advantages by combining the benefits of GLP-1, GIP, and glucagon agonism.