Glucagon-like Peptide-1 Receptor Agonists and Dual Incretin Therapies Across HFpEF and Cardiovascular Outcomes Trials in Patients with Obesity

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and emerging dual incretin therapies have demonstrated substantial effects on weight reduction and metabolic improvement, with growing evidence supporting favorable cardiovascular outcomes. This narrative review provides a focused overview of key cardiovascular outcomes trials (CVOTs) and HFpEF-oriented clinical studies evaluating GLP-1 RA and dual incretin therapies in patients living with obesity, including completed and ongoing investigations. We summarize trial characteristics, critically appraise their outcomes, and briefly discuss mechanistic pathways potentially linking incretin-based therapies to cardiovascular and HFpEF-related benefits. Because available data derive from heterogeneous study designs, we explicitly distinguish evidence from type 2 diabetes cardiovascular outcomes trials, obesity-without-diabetes cardiovascular outcomes trials, HFpEF-specific randomized trials, mechanistic substudies, ongoing trials, and real-world observational analyses. We also situate incretin-based therapies within contemporary obesity, diabetes, cardiovascular, and HFpEF guideline-directed care. Finally, we identify current knowledge gaps, future research priorities, and innovative approaches needed to refine personalized therapeutic strategies and optimize patient-centered outcomes in obesity-associated HFpEF.