Semaglutide for Symptom Management in HFpEF and Related Metabolic Phenotypes

Written by Alex Flores-Xie, PharmD Candidate and Adenike Atanda-Oshikoya, PharmD, BCACP, CDCES, CTTS

HFpEF: A Growing Challenge

Heart Failure (HF) is a heterogenous syndrome defined by structural or functional cardiac abnormalities impairing the heart’s ability to meet metabolic demands.(1,2) HF is classified by left-ventricular ejection fraction (LVEF) into: HF with reduced EF (HFrEF, LVEF <40%), HF with preserved EF (HFpEF, LVEF ≥50%), HF with mildly reduced EF (HFmrEF, LVEF 41-49%) and HF with improved EF (HFimpEF, LVEF baseline ≤40% with ≥10-point increase to LVEF >40%).(1)

With over 80% of patients with HFpEF being overweight or obese, this phenotype accounts for most HF cases in the United States and continues to rise in prevalence.(3) Obesity worsens clinical outcomes via cardiac adverse remodeling.(4) Excess adiposity contributes to HFpEF progression through increased leptin levels, reduced natriuretic peptides, and activation of the renin-angiotensin-aldosterone system (RAAS), leading to systemic inflammation, cardiac fibrosis, and arterial stiffness.(3) Patients with HFpEF, obesity, and diabetes experience greater adverse hemodynamics, worse functional capacity, and quality of life.(4) HFpEF, accounts for up to 50% of HF hospitalizations.(2) Hospitalized patients are often older females with obesity, type 2 diabetes mellitus (T2DM), hypertension, atrial fibrillation, and chronic kidney disease. These comorbidities have an influential effect on outcomes, possibly leading to HFpEF-associated mortality ranging from 15% at one year to 75% at five to ten years after hospitalization.(2) Unlike HFrEF, HFpEF lacks proven survival benefits from guideline directed medical therapy (GDMT). Trials such as TOPCAT and PARAGON-HF failed to meet hospitalization reduction primary endpoints in patients with HFpEF.(5,6) However, the EMPEROR-Preserved and DELIVER trials led the ACC/AHA/HFSA to recommend the sodium glucose-cotransporter 2 (SGLT2) inhibitors, empagliflozin and dapagliflozin, for hospitalization reduction in HFpEF.(7-9)

Semaglutide’s Role in HFpEF

Semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1 RA) enhances glucose-dependent insulin secretion, suppresses inappropriate glucagon release, and slows gastric emptying.(10) GLP-1 RAs, including liraglutide, dulaglutide, and semaglutide significantly improve glycemic control, promote weight loss, and reduce atherosclerotic cardiovascular and renal risk.(11) Among the approved GLP-1 RAs in the United States, semaglutide and tirzepatide, a dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 RA, have emerged as possible therapies for patients with HFpEF.(12-14) These agents may improve physical function and enhance quality of life by reducing adiposity, leptin levels, and RAAS activation. Recognizing the strong link between obesity, T2DM, and HFpEF, the 2025 American Diabetes Association (ADA) Standards of Care granted a Level A recommendation for GLP-1 RAs with demonstrated benefit, specifically semaglutide, for reducing HF symptoms and physical limitations in patients with T2DM and obesity.(11) More recently, the SUMMIT trial showed that tirzepatide significantly reduced the composite risk of major HF events, including hospitalization and cardiovascular (CV) death, suggesting that dual GIP/GLP-1 agonism may further optimize outcomes.(14) However, the 2025 ADA Standards of Care reference only semaglutide as the GLP-1 RA with demonstrated benefit based on the evidence from the STEP-HFpEF trial program. The omission of tirzepatide from the guidelines is likely attributable to the ADA’s evidence cutoff occurring prior to the publication of SUMMIT in The New England Journal of Medicine on January 30, 2025.

Clinical Implications

The STEP-HFpEF trial program, which includes STEP-HFpEF (in patients with HFpEF and obesity) and STEP-HFpEF DM (in patients with HFpEF, obesity, and T2DM) demonstrated significant benefits of weekly subcutaneous semaglutide 2.4 mg, improving physical function, alleviating symptoms, and promoting weight loss with potential disease-modifying effects.(12,13) The dual primary endpoints of change in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS) and percentage weight loss at 52 weeks drove the positive results of the trials. Confirmatory secondary endpoints, including 6-minute walk distance and C-reactive protein levels, further supported semaglutide’s efficacy.(12,13) While not powered for mortality or HF hospitalization, exploratory analyses suggest benefits beyond weight loss alone.(4,12) An echocardiography substudy further explored semaglutide’s potential disease-modifying mechanisms in HFpEF pathophysiology in detail.(4) A comparison of key clinical trials with agents demonstrating benefit in HFpEF can be found in Table 1.

Table 1. Key Clinical Trials of Therapies Demonstrating Benefit in HFpEF (7,8,12-14)

A New Era in HFpEF Management

Semaglutide offers significant benefits for patients with HFpEF, obesity, and T2DM, especially those at high CV risk.(12,13) Exploratory analyses suggest improvements in congestion, vascular and skeletal muscle function, mitochondrial efficiency, epicardial adipose tissue reduction, inflammation, and insulin resistance.(4) Loop diuretics remain essential for acute decompensation and symptom management but increase the risk of electrolyte and volume disturbances and renal dysfunction with chronic use.(2) While both diuretics and semaglutide alleviate congestion in HFpEF, semaglutide uniquely demonstrates clinically meaningful improvements in quality of life.(12,13) However, when compared to loop diuretics like furosemide, the high cost of semaglutide remains a barrier.(15) Current evidence, particularly from the echocardiographic substudies of the STEP-HFpEF trial program, suggests that semaglutide’s effects on congestion may extend beyond weight loss alone. Although these effects cannot yet be confidently attributed to direct fluid removal, as seen with loop diuretics, the observed improvements in cardiac structure and function raise the possibility of disease-modifying effects.(4) Further mechanistic studies are needed to clarify this distinction.

While SGLT2 inhibitors remain the cornerstone for reducing HF hospitalizations, semaglutide offers complementary benefits.(9) Future research should evaluate combination therapy of SGLT2 inhibitors with GLP-1 RAs, compare GLP-1 agonism to other HFpEF therapies, and provide long-term mortality data. Cost effective strategies are also necessary to improve accessibility. The most promising approach to addressing the growing burden of HFpEF may be a personalized treatment strategy targeting high-risk metabolic phenotypes with a combination of SGLT2 inhibitors and GLP-1 RAs.

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1. Universal Definition and Classification of Heart Failure: A Step in the Right Direction from Failure to Function - American College of Cardiology. American College of Cardiology. Published July 12, 2021. https://www.acc.org/Latest-in-Cardiology/Articles/2021/07/12/12/31/Universal-Definition-and-Classification-of-Heart-Failure.

2. Cannata A, McDonagh TA. Heart Failure with Preserved Ejection Fraction. N Engl J Med. 2025;392(2):173-184. doi:10.1056/NEJMcp2305181.

3. Physical activity and obesity in HFPEF - American College of Cardiology. American College of Cardiology. Published December 6, 2018. https://www.acc.org/latest-in-cardiology/ten-points-to-remember/2018/12/06/14/32/physical-activity-fitness-and-obesity-in-heart.

4. Solomon SD, Ostrominski JW, Wang X, et al. Effect of semaglutide on cardiac structure and function in patients with Obesity-Related Heart Failure. Journal of the American College of Cardiology. 2024;84(17):1587-1602. doi:10.1016/j.jacc.2024.08.021.

5. Pitt B, Pfeffer MA, Assmann SF, et al. Spironolactone for Heart Failure with Preserved Ejection Fraction. N Engl J Med. 2014;370(15):1383-1392. doi:10.1056/NEJMoa1313731.

6. Solomon SD, McMurray JJV, Anand IS, et al. Angiotensin–Neprilysin Inhibition in Heart Failure with Preserved Ejection Fraction. N Engl J Med. 2019;381(17):1609-1620. doi:10.1056/NEJMoa1908655.

7. Anker SD, Butler J, Filippatos G, et al. Empagliflozin in Heart Failure with a Preserved Ejection Fraction. N Engl J Med. 2021;385(16):1451-1461. doi:10.1056/NEJMoa2107038.

8. Solomon SD, McMurray JJV, Claggett B, et al. Dapagliflozin in Heart Failure with Mildly Reduced or Preserved Ejection Fraction. N Engl J Med. 2022;387(12):1089-1098. doi:10.1056/NEJMoa2206286.

9. Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2022;145(18). doi:10.1161/cir.0000000000001063.

10. Semaglutide. Lexi-drugs. UpToDate Lexidrug. UpToDate Inc. Riverwoods, IL. Accessed April 3, 2025. http://online.lexi.com.

11. American Diabetes Association Professional Practice Committee; 10. Cardiovascular Disease and Risk Management: Standards of Care in Diabetes—2025. Diabetes Care 1 January 2025; 48 (Supplement_1): S207–S238. https://doi.org/10.2337/dc25-S010.

12. Kosiborod MN, Abildstrøm SZ, Borlaug BA, et al. Semaglutide in Patients with Heart Failure with Preserved Ejection Fraction and Obesity. N Engl J Med. 2023;389(12):1069-1084. doi:10.1056/NEJMoa2306963.

13. Kosiborod MN, Petrie MC, Borlaug BA, et al. Semaglutide in Patients with Obesity-Related Heart Failure and Type 2 Diabetes. N Engl J Med. 2024;390(15):1394-1407. doi:10.1056/NEJMoa2313917.

14. Packer M, Zile MR, Kramer CM, et al. Tirzepatide for Heart Failure with Preserved Ejection Fraction and Obesity. N Engl J Med. Published online November 16, 2024. doi:10.1056/NEJMoa2410027.

15. Furosemide. Lexi-drugs. UpToDate Lexidrug. UpToDate Inc. Riverwoods, IL. Accessed April 3, 2025. http://online.lexi.com. 

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Alex Flores-Xie

PharmD Candidate 2026

University of North Texas

Health Science Center College of Pharmacy

Fort Worth, TX

Adenike Atanda, PharmD, BCACP, CDCES, CTTS

Assistant Dean of Pharmacy Student Success and Academic Performance - Office of Pharmacy Student Success

Director of Introductory Pharmacy Practice Experiences - Office of Experiential Education

Associate Professor of Pharmacotherapy

University of North Texas

Health Science Center College of Pharmacy

Fort Worth, TX