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

Oct 29, 2025Current heart failure reports

New Treatments for Heart Failure Linked to Obesity

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Abstract

Incretin-based therapies could significantly improve heart failure symptoms and induce weight loss in obese patients with heart failure with preserved ejection fraction (HFpEF).

Bariatric surgery leads to the most substantial and lasting weight loss but has not been evaluated in randomized trials specifically for HFpEF outcomes.
Recent trials show that glucagon-like peptide-1 receptor agonists and dual receptor agonists can alleviate symptoms and slow heart failure progression in obese HFpEF patients, regardless of diabetes.
Sodium-glucose cotransporter-2 inhibitors and nonsteroidal mineralocorticoid receptor antagonists may provide prognostic advantages in HFpEF, especially for individuals with higher body mass index (BMI).
Angiotensin receptor-neprilysin inhibitors and the controlled metabolic accelerator HU6 currently lack randomized trial support for their use in this population.
A combination of incretin-based therapies, SGLT2 inhibitors, and non-steroidal MRAs may be the most effective strategy available for managing obesity-related HFpEF.

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PURPOSE OF 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 FINDINGS: 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.

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

Abstract

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