Glucagon-Like Peptide-1 Receptor Agonists Improve Cardiovascular Outcomes in Heart Failure with Preserved Ejection Fraction, Independent of Diabetes: A Systematic Review and Meta-Analysis

Background: Heart failure with preserved or mildly reduced ejection fraction (HFpEF/HFmrEF), is often associated with obesity and metabolic dysfunction.Recent data suggests that incretin-based therapies, including GLP-1 receptor agonists (GLP-1RAs) and tirzepatide improve cardiovascular outcomes in HFpEF/HFmrEF in both patients with and without diabetes.However, whether the effects differ by diabetes status across the broader literature remains unclear.Methods: MEDLINE and Embase were searched through October 2025 to identify randomized controlled trials (RCTs), post-hoc RCT analyses, and observational studies evaluating GLP-1RAs and tirzepatide on cardiovascular outcomes in HFpEF/HFmrEF.Meta-regression examined effect modification by type 2 diabetes (T2D) status.Exploratory network metaanalysis (NMA) of RCTs was performed to evaluate comparative efficacy across therapies.Results: Eleven studies met inclusion criteria.In a meta-regression of RCTs, all p-values for interaction were >0.05, indicating no evidence that T2D modified treatment effects.In pooled RCT analyses, incretin-based therapies significantly reduced HF hospitalization/events (HR 0.68 [95% CI 0.52-0.88])and composite of CV death or HF hospitalization/events (HR 0.76 [95% CI 0.65-0.87]).Pooled observational data demonstrated significant reduction in HF hospitalization/events (HR 0.60 [95% CI 0.58-0.62]).Exploratory NMA found no significant difference in efficacy between individual agents. J o u r n a l P r e -p r o o fConclusions: Incretin-based therapies with GLP-1RA activity reduce HF hospitalization/events in HFpEF/HFmrEF, with comparable benefits irrespective of T2D status.These findings support cardiovascular benefits of incretin-based therapies beyond glucose lowering and reinforce their role in obesity-associated HFpEF/HFmrEF.