GLP-1 Receptor Agonists Improve Heart Failure with Preserved Ejection Fraction Outcomes and Reveal Cardioprotective Mechanisms

Despite significant advancements, heart failure (HF) remains a leading cause of morbidity and mortality, particularly heart failure with preserved ejection fraction (HFpEF), for which effective pharmacotherapies are limited. Current standard-of-care often addresses symptoms rather than underlying pathology, leaving a substantial treatment gap. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), initially developed for type 2 diabetes, have demonstrated robust cardiovascular (CV) benefits, including reducing major adverse cardiovascular events (MACE). However, their precise role and mechanisms across the heterogeneous spectrum of HF, especially distinguishing between HFpEF and heart failure with reduced ejection fraction (HFrEF), require comprehensive review to guide clinical application.

This two-part review synthesized randomized evidence comparing GLP-1 receptor agonists with placebo in adults diagnosed with heart failure across various ejection fraction phenotypes. Researchers systematically examined findings from major clinical trials and their substudies, focusing on outcomes such as major adverse cardiovascular events (MACE), symptom burden, exercise tolerance, and quality of life. The review also delved into the physiological mechanisms by which GLP-1RAs exert their cardioprotective effects, including actions independent of glycemic control and their potential to overcome vascular regenerative dysfunction, drawing from emerging evidence.

GLP-1 RAs significantly reduce symptom burden, increase exercise tolerance, and improve quality of life specifically in patients with heart failure with preserved ejection fraction (HFpEF). > Notably, these beneficial effects were observed in HFpEF but were not evident in patients with heart failure with reduced ejection fraction (HFrEF), highlighting a phenotype-specific response. The review confirmed that GLP-1 RAs reduce major adverse cardiovascular events (MACE) in patients with type 2 diabetes and atherosclerotic cardiovascular disease. Furthermore, semaglutide specifically demonstrated protection against MACE in individuals with obesity and established cardiovascular disease, even in the absence of type 2 diabetes. The article elucidated various mechanisms contributing to this cardiovascular protection, including actions that are independent of glycemic control and emerging evidence suggesting GLP-1RAs can overcome vascular regenerative dysfunction, contributing to their broad CV benefits.