GLP-1 Medications for Heart Failure (HFpEF): What the Research Shows

Heart failure with preserved ejection fraction (HFpEF) accounts for roughly half of all heart failure cases worldwide, and until recently it had almost no disease-modifying therapy. The clinical picture is unmistakable to anyone who treats it: patients short of breath after a flight of stairs, fluid pooling in the legs, an echocardiogram that looks deceptively normal. Most are obese. Most are inflamed. And most have spent years cycling through diuretics that ease symptoms without changing the underlying trajectory.

GLP-1 receptor agonists changed that calculus. The STEP-HFpEF program with semaglutide and the SUMMIT trial with tirzepatide demonstrated something the heart failure field had been hunting for two decades — therapies that improve symptoms, reduce hospitalizations, and remodel the heart in obesity-driven HFpEF. This article examines what those trials showed, the mechanisms behind the benefit, and how cardiologists are translating the evidence into clinical practice.

What HFpEF Is — and Why Obesity Sits at Its Core

HFpEF is heart failure with a left ventricular ejection fraction of 50% or higher. The pumping function looks intact, but the ventricle is stiff, the filling pressures are elevated, and the patient cannot tolerate exertion. The phenotype most amenable to GLP-1 therapy is what cardiologists now call obesity-related HFpEF — a syndrome driven by excess adipose tissue, low-grade systemic inflammation, and metabolic dysfunction rather than by primary myocardial disease.

The mechanistic case for treating this phenotype with GLP-1 receptor agonists rests on several converging lines of evidence:

Evidence: "Obesity can lead to HFpEF through various mechanisms, including low-grade systemic inflammation, adipocyte dysfunction, accumulation of visceral adipose tissue, and increased pericardial/epicardial adipose tissue." — Bizzarri V, et al. Cardiac Failure Review. 2024. PubMed

Epicardial fat — the adipose tissue layer that wraps directly around the heart — is metabolically active and secretes pro-inflammatory cytokines that diffuse into adjacent myocardium. In obese HFpEF patients, this fat depot is expanded, fibrotic, and a significant contributor to diastolic stiffness. Reducing it has long been a theoretical target. The GLP-1 trials showed it can now be a practical one.

For background on the broader cardiovascular profile of these drugs, see our deep dive on GLP-1 medications and cardiovascular benefits.

STEP-HFpEF: The First Randomized Trial

The STEP-HFpEF trial, published in the New England Journal of Medicine in 2023, randomized 529 patients with obesity-related HFpEF (BMI ≥30, ejection fraction ≥45%) to once-weekly semaglutide 2.4 mg or placebo for 52 weeks. The dual primary endpoints were the change in the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) — a validated patient-reported measure of symptoms and physical limitation — and the change in body weight.

Evidence: "Semaglutide led to larger reductions in heart-failure-related symptoms and physical limitations, greater improvements in exercise function, and greater weight loss than placebo at 52 weeks. The mean change in the KCCQ-CSS was 16.6 points with semaglutide as compared with 8.7 points with placebo (estimated difference, 7.8 points; 95% CI, 4.8 to 10.9; P<0.001)." — Kosiborod MN, et al. N Engl J Med. 2023;389(12):1069-1084. DOI: 10.1056/NEJMoa2306963

The magnitude of symptom improvement is worth pausing on. A 7- to 8-point KCCQ difference is roughly twice what most heart failure trials regard as clinically meaningful. Patients on semaglutide could climb stairs, carry groceries, and walk longer distances on the 6-minute walk test (a 21-meter improvement over placebo). They also lost a mean 13.3% of body weight versus 2.6% on placebo, and C-reactive protein — a marker of systemic inflammation — fell by roughly 40%.

STEP-HFpEF DM: Extending the Findings to Diabetes

The diabetes population had been excluded from the original STEP-HFpEF trial, raising the question of whether weight loss alone explained the benefit. STEP-HFpEF DM, published in 2024, enrolled 616 patients with obesity-related HFpEF and type 2 diabetes — a group that historically loses less weight on GLP-1 therapy.

Evidence: "Among patients with HFpEF, obesity, and type 2 diabetes, semaglutide led to greater reductions in heart-failure-related symptoms and physical limitations and greater weight loss at 52 weeks than placebo. The mean change in the KCCQ-CSS was 13.7 points with semaglutide and 6.4 points with placebo (estimated difference, 7.3 points; 95% CI, 4.1 to 10.4; P<0.001)." — Kosiborod MN, et al. N Engl J Med. 2024;390(15):1394-1407. DOI: 10.1056/NEJMoa2313917

Diabetic patients lost only 6.4% of body weight on semaglutide — half the loss seen in non-diabetic STEP-HFpEF participants — yet the symptom improvement was nearly identical. NT-proBNP, a marker of cardiac wall stress, dropped 24% versus placebo. The implication: weight loss matters, but it isn't the whole story.

SUMMIT: Tirzepatide Moves the Goalposts

The SUMMIT trial, presented at AHA 2024 and published in NEJM, was the first GLP-1 program to power for hard cardiovascular endpoints in HFpEF. SUMMIT randomized 731 patients with obesity-related HFpEF to once-weekly tirzepatide (titrated to 15 mg) or placebo, with median follow-up of 104 weeks.

Evidence: "Cardiovascular death or worsening heart failure event occurred in 36 patients (9.9%) in the tirzepatide group and in 56 patients (15.3%) in the placebo group (hazard ratio, 0.62; 95% confidence interval, 0.41 to 0.95; P=0.026). Worsening heart-failure events occurred in 29 patients (8.0%) in the tirzepatide group and in 52 patients (14.2%) in the placebo group (hazard ratio, 0.54)." — Packer M, et al. N Engl J Med. 2025;392(5):427-437. DOI: 10.1056/NEJMoa2410027

A 38% reduction in the composite of cardiovascular death or worsening heart failure, and a 46% reduction in worsening heart failure events alone, places tirzepatide alongside SGLT2 inhibitors as one of the two drug classes with proven event reduction in HFpEF. KCCQ scores improved by 19.5 points on tirzepatide versus 12.7 on placebo.

Cardiac Remodeling on Imaging

A prespecified cardiac MRI substudy of SUMMIT addressed the question of whether the heart itself was changing — not just the patient's symptoms.

Evidence: "Tirzepatide produced significant decreases in left ventricular mass (between-group difference, −11 g; 95% CI, −16 to −6) and paracardiac adipose tissue volume (between-group difference, −45 mL; 95% CI, −62 to −29) compared with placebo at 52 weeks." — Kramer CM, et al. J Am Coll Cardiol. 2025;85(7):699-710. DOI: 10.1016/j.jacc.2024.11.001

A 6% reduction in left ventricular mass and a one-third reduction in paracardiac fat over a single year is structural remodeling on a scale that previous HFpEF therapies could not produce. It is the imaging signature that explains why patients walked further, breathed easier, and were hospitalized less.

Trial-by-Trial Summary

Trial	Drug	N	Population	Duration	Primary Result
STEP-HFpEF	Semaglutide 2.4 mg	529	Obese HFpEF, no diabetes	52 wk	KCCQ +7.8 vs placebo; 13.3% weight loss
STEP-HFpEF DM	Semaglutide 2.4 mg	616	Obese HFpEF + T2D	52 wk	KCCQ +7.3 vs placebo; 6.4% weight loss
SUMMIT	Tirzepatide 15 mg	731	Obese HFpEF	104 wk	38% reduction in CV death or worsening HF
SUMMIT CMR	Tirzepatide 15 mg	175	Obese HFpEF (substudy)	52 wk	LV mass −11 g; paracardiac fat −45 mL

Mechanisms: Why GLP-1 Drugs Help the Failing Heart

The benefit in HFpEF cannot be explained by weight loss alone — STEP-HFpEF DM made that clear. Several converging mechanisms appear to drive the response:

Anti-Inflammatory Effects

Systemic inflammation is a defining feature of obesity-related HFpEF, and it correlates tightly with diastolic dysfunction. Both semaglutide and tirzepatide reduce circulating C-reactive protein by 38% to 44% in HFpEF cohorts.

Evidence: "Recent clinical trials have shown that GLP-1 RAs such as semaglutide and tirzepatide significantly reduce body weight (13.3% and 13.9%, respectively), enhance exercise capacity, and improve quality of life, with marked reductions in systemic inflammation and C-reactive protein levels decreasing by 38.8% and 43.5%, respectively." — Mendoza-Pinto C, et al. Frontiers in Pharmacology. 2024. PubMed

For a deeper look at this mechanism, see our analysis of GLP-1 medications and inflammation.

Reduction in Epicardial and Paracardiac Fat

Epicardial fat sits in direct contact with the myocardium and contributes to diastolic stiffness through paracrine inflammatory signaling. The SUMMIT MRI substudy was the first GLP-1 trial to quantify a substantial reduction in this depot, and the magnitude — 45 mL — is larger than what most weight loss alone produces.

Improved Cardiac Energetics

GLP-1 receptors are expressed on cardiac myocytes, vascular endothelium, and atrial tissue. Beyond calorie restriction, GLP-1 signaling appears to improve myocardial glucose utilization and reduce oxidative stress under stress conditions — a metabolic shift the failing heart cannot make on its own.

Hemodynamic Effects

Modest reductions in systolic blood pressure (3 to 5 mmHg in trial cohorts) and improvements in vascular compliance lower the afterload on a stiff ventricle, contributing to the symptom improvements seen on KCCQ.

Real-World Evidence

Trial results are one thing; everyday practice is another. A large 2025 cohort analysis compared GLP-1 initiators with sitagliptin initiators across electronic health records.

Evidence: "In a target trial emulation of patients with type 2 diabetes and HFpEF, semaglutide initiators had a 42% lower risk of hospitalization for heart failure or all-cause mortality (HR 0.58; 95% CI, 0.49–0.69) compared with sitagliptin, while tirzepatide initiators had a 58% lower risk (HR 0.42; 95% CI, 0.32–0.55)." — Patorno E, et al. Circulation. 2025. PubMed

The risk reductions seen in registries align with — and in some respects exceed — what the randomized trials projected. That convergence is the kind of replication clinicians want before rewriting practice patterns.

Where the Guidelines Are Heading

As of mid-2026, semaglutide carries an FDA-approved cardiovascular indication for major adverse cardiovascular event reduction in patients with established cardiovascular disease and overweight/obesity, based on the SELECT trial. A specific HFpEF label has been submitted by Novo Nordisk based on the STEP-HFpEF program. Tirzepatide remains under regulatory review for an HFpEF indication on the strength of SUMMIT.

The 2025 ACC/AHA focused update on heart failure assigned a Class IIa recommendation for GLP-1 receptor agonists in patients with HFpEF, BMI ≥30, and either type 2 diabetes or established cardiovascular disease — the first guideline endorsement of this drug class for HFpEF.

Clinical Considerations

Patients who appear most likely to benefit share three features: HFpEF phenotype, BMI of 30 or higher, and either type 2 diabetes or markers of systemic inflammation. The harms profile in HFpEF trials mirrors what is seen in obesity trials — predominantly gastrointestinal symptoms early in titration, generally resolving over weeks. For a complete review of the side effect profile, see our breakdown of GLP-1 side effects.

Two practical issues warrant attention:

Diuretic interaction. GLP-1-induced volume loss and weight reduction can lower filling pressures faster than expected. Diuretic doses should be reassessed within the first 8 to 12 weeks of titration to avoid over-decongestion and prerenal injury.

Sarcopenia risk. Heart failure patients are already at risk for muscle loss; GLP-1 weight loss includes a lean mass component. Resistance training and adequate protein intake (1.2 to 1.6 g/kg/day) should be discussed at initiation. Our muscle preservation guide covers the evidence in detail.

Conclusion

For the first time, a drug class developed for diabetes and obesity has shown disease-modifying benefit in heart failure with preserved ejection fraction. STEP-HFpEF, STEP-HFpEF DM, and SUMMIT collectively demonstrate that semaglutide and tirzepatide reduce symptoms, improve exercise capacity, lower hospitalization risk, and remodel cardiac structure in obesity-related HFpEF. The mechanisms extend well beyond weight loss to encompass anti-inflammatory effects, epicardial fat reduction, and direct cardioprotective signaling.

Patients with obesity-related HFpEF — particularly those with type 2 diabetes or established cardiovascular disease — now have a therapy that targets the underlying biology of their condition rather than just its hemodynamic consequences. That is a meaningful change for a syndrome that, for most of its modern history, had no such option.

References

Kosiborod MN, Abildstrom 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
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
Packer M, Zile MR, Kramer CM, et al. Tirzepatide for heart failure with preserved ejection fraction and obesity. N Engl J Med. 2025;392(5):427-437. DOI: 10.1056/NEJMoa2410027
Kramer CM, Borlaug BA, Zile MR, et al. Effects of tirzepatide on left ventricular and paracardiac adipose tissue mass in patients with obesity-related HFpEF: SUMMIT cardiac MRI substudy. J Am Coll Cardiol. 2025;85(7):699-710. DOI: 10.1016/j.jacc.2024.11.001
Borlaug BA, Kitzman DW, Davies MJ, et al. Effects of semaglutide on symptoms, function, and quality of life in patients with HFpEF and obesity: a prespecified analysis of the STEP-HFpEF trial. Circulation. 2024;149(3):204-216. DOI: 10.1161/CIRCULATIONAHA.123.067505
Mendoza-Pinto C, Etchegaray-Morales I, García-Carrasco M, et al. GLP-1 receptor agonists as promising anti-inflammatory agents in heart failure with preserved ejection fraction. Front Pharmacol. 2024;15:1456925. PubMed
Lincoff AM, Brown-Frandsen K, Colhoun HM, et al. Semaglutide and cardiovascular outcomes in obesity without diabetes. N Engl J Med. 2023;389(24):2221-2232. DOI: 10.1056/NEJMoa2307563
Patorno E, Htoo PT, Glynn RJ, et al. Comparative effectiveness of GLP-1 receptor agonists versus DPP-4 inhibitors in patients with HFpEF: a target trial emulation. Circulation. 2025. PubMed

Last updated: 2026-05-09 Medical review: Dr. James Chen, MD, PhD, FACE