Advances in Pharmacotherapies for Obesity-Related HFpEF: A Comprehensive Review

The global obesity epidemic has precipitated a surge in obesity-related heart failure with preserved ejection fraction (HFpEF), a distinct clinical phenotype characterized by exacerbated symptom burden, systemic inflammation, and impaired quality of life compared to non-obese HFpEF. While lifestyle modifications remain foundational, suboptimal adherence limits their efficacy. Bariatric surgery leads to the most dramatic and sustained weight loss but lacks a randomized trial for HFpEF-specific outcomes.

Recent landmark trials (STEP-HFpEF, STEP-HFpEF DM, SUMMIT) demonstrate that incretin-based therapies-glucagon-like peptide-1 receptor agonists (GLP-1RAs) and dual glucose-dependent insulinotropic polypeptide/GLP-1 receptor agonists-significantly ameliorate heart failure symptoms, attenuate heart failure worsening, and induce weight loss in obese HFpEF patients, irrespective of diabetes status. However, long-term cardiovascular mortality benefits and safety profiles require further validation. Sodium-glucose cotransporter-2 inhibitors and nonsteroidal mineralocorticoid receptor antagonists MRAs exhibit prognostic benefits in HFpEF, with post hoc analyses suggesting enhanced efficacy in higher BMI subgroups. Conversely, angiotensin receptor-neprilysin inhibitors and the controlled metabolic accelerator HU6 lack randomized trials to support routine use. A combination of incretin-based therapies, SGLT2 inhibitors, and non-steroidal MRAs may represent the optimal evidence-based strategy for obesity-related HFpEF at present. Future research should prioritize standardized definitions of obesity, BMI thresholds, weight loss targets, optimal combination strategies, and long-term outcome assessments.