Glucagon-like peptide-1 receptor agonists and obesity paradox in heart failure with preserved ejection fraction: a systematic review

Abstract

Heart failure with preserved ejection fraction (HFpEF) is associated with obesity, inflammation, and cardiac metabolism. While obesity contributes to HFpEF, the ‘obesity paradox’ suggests that higher BMI may correlate with better outcomes. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have cardiovascular benefits through weight loss, anti-inflammatory effects, and improved myocardial function. This systematic review involved randomized trials and cohort studies from 2015 to 2024, assessing GLP-1 RAs in patients with obese HFpEF (BMI ≥ 30 kg/m²). Outcomes included heart failure hospitalizations, mortality, exercise capacity, and quality of life. Eighteen studies involved over 22 000 participants. GLP-1 RAs, especially semaglutide and tirzepatide, consistently reduced weight, inflammation (C-reactive protein), and myocardial stress (N-terminal pro B-type natriuretic peptide) while improving 6-min walk distance and Kansas City Cardiomyopathy Questionnaire scores, uniformly across BMI groups. GLP-1 RAs counter the metabolic burden of obesity in HFpEF while preserving hemodynamic benefits, offering a promising therapeutic option.