The landscape of heart failure with preserved ejection fraction (HFpEF) is evolving—particularly in patients with obesity and type 2 diabetes (T2D).

Until recently, treatment options remained limited. Now, two incretin-based therapies—semaglutide and tirzepatide—are showing unprecedented benefits in this complex phenotype.

Recent findings from the SUMMIT trial (tirzepatide) and the STEP-HFpEF program (semaglutide) shed new light on their therapeutic potential. But how do they compare?

Pathophysiology Primer: Why Target Incretin Pathways in HFpEF?

HFpEF is increasingly recognized as a systemic cardiometabolic disorder. It’s characterized by:

• Diastolic dysfunction
• Endothelial inflammation
• Visceral adiposity
• Reduced exercise capacity

These processes are deeply intertwined with obesity, insulin resistance, and chronic inflammation—precisely the domains influenced by GLP-1 and GIP signaling.

Tirzepatide (GIP/GLP-1 RA): Evidence from the SUMMIT Trial

Design: Phase 3, randomized, placebo-controlled

Population: HFpEF + obesity

Outcomes:

• Reduced HF hospitalizations and CV death
• Substantial weight loss, especially visceral fat
• Improved exercise capacity (6MWT, KCCQ scores)
• Favorable cardiac remodeling (↓ LV mass, epicardial fat; ↑ diastolic function)

Mechanistic Highlights:

• Dual incretin agonism improves insulin sensitivity, lowers systemic inflammation, and reduces cardiac fat load
• Positive effects seen across BMI ranges, not just in morbid obesity

Semaglutide (GLP-1 RA): Evidence from STEP-HFpEF and SELECT

STEP-HFpEF / HFpEF-DM:

Hair Removing Hard Beans Wax Painless Beauty Wax Beans For All Skins Wax Beans For Face Body Legs

• Showed improved symptoms, physical function, and weight loss
• Reduced CRP, suggesting anti-inflammatory benefits
• Focused on functional outcomes (KCCQ, 6MWT), not hard CV endpoints

SELECT trial (non-HF population):

• Demonstrated 20% MACE reduction in obese, high-CV-risk patients without T2D

Clinical Implication:

Semaglutide is well-supported for HFpEF with obesity, particularly when symptom relief and physical function are priorities.

Tirzepatide vs. Semaglutide in HFpEF: Head-to-Head Summary

Clinical Takeaways:

• Both agents improve symptoms and functional status in HFpEF with obesity.
• Tirzepatide now has hard CV outcome data in HFpEF from SUMMIT—an important advantage.
• Semaglutide has robust real-world use, strong MACE data, and good tolerability.

Who might benefit most?

• For HFpEF + obesity + CV symptoms: Tirzepatide may offer greater disease modification

• For HFpEF + frailty or early obesity: Semaglutide may provide more gradual, symptom-focused relief

Conclusion: Tailoring Therapy for the Cardiometabolic Patient

We are entering a new era of HFpEF management, where metabolic therapies play a central role. Both semaglutide and tirzepatide offer hope for a condition once viewed as untreatable.

With tirzepatide now showing reductions in HF hospitalizations and CV death, it may soon redefine the standard of care—especially for obese patients with functional limitations.

Still, long-term head-to-head studies and more diverse HF populations are needed. Until then, treatment should be personalized based on:

• Comorbidities (T2D, obesity severity)
• Symptom burden
• Access and cost
• Risk profile

References:

• JAMA. 2024; SUMMIT Trial Results.
• NEJM. 2023; STEP-HFpEF.
• SELECT Trial Investigators. 2023.
• SURPASS-CVOT (Ongoing).
• J Diabesity; Tirzepatide for Heart Failure
•