GLP-1 for Treatment of Heart Failure

Glucagon-like peptide-1 (GLP-1) receptor agonists show particular promise in heart failure with preserved ejection fraction (HFpEF), especially among patients with obesity-related disease. The STEP-HFpEF trials demonstrate that substantial weight reduction achieved with once-weekly semaglutide or tirzepatide correlates with improvements in heart failure–related outcomes, functional capacity, and exercise tolerance. Meta-analyses of available data suggest potential signals for reduced cardiovascular events including heart failure hospitalizations, though definitive evidence requires larger dedicated trials.

The mechanistic rationale for GLP-1 therapy in HFpEF centers on addressing central adiposity, which may drive disease progression through “angry adipocyte” pathophysiology. By targeting obesity as a fundamental driver of HFpEF, these agents potentially address root causes rather than just symptoms. Additional benefits include improvements in comorbid conditions like sleep apnea and other obesity-related complications that contribute to heart failure progression.

Application in heart failure with reduced ejection fraction (HFrEF) requires more caution due to limited dedicated trial data and some concerning signals. The FIGHT trial showed potential signals for increased heart failure hospitalizations with liraglutide in hospitalized patients with HFrEF, though post hoc analyses of cardiovascular outcome trials suggest benefits may still exist in ambulatory, stable patients. Potential concerns include heart rate increases and arrhythmic risks, necessitating careful patient selection. However, for patients with compelling indications like obesity or diabetes, the SELECT trial subgroup data suggest HFrEF should not preclude GLP-1 therapy initiation when otherwise appropriate.