GLP-1 Medications and Heart Failure: What the STEP-HFpEF and SUMMIT Trials Reveal

*This article is for informational and educational purposes only. It is not medical advice. Compounded semaglutide and tirzepatide are not FDA-approved medications. The clinical research cited here was conducted using FDA-approved branded formulations. Results from studies of FDA-approved medications may not apply to compounded products. Individual results vary. Consult your licensed healthcare provider and cardiologist before starting, stopping, or adjusting any medication.*

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Heart failure affects more than six million Americans, and roughly half of those cases involve a form called heart failure with preserved ejection fraction, or HFpEF. For years, this condition was one of cardiology's most frustrating challenges: the heart appears to pump normally on imaging, yet patients struggle to climb stairs, feel constantly breathless, and face repeated hospitalizations.

Obesity is one of the most powerful drivers of HFpEF. Excess weight strains the heart mechanically, promotes systemic inflammation, and deposits fat in and around cardiac tissue. Until recently, weight loss was easy to recommend and nearly impossible to achieve at a meaningful scale. GLP-1 receptor agonists changed that equation, which is why cardiologists and obesity medicine specialists are paying close attention to two trials published in the New England Journal of Medicine: STEP-HFpEF and SUMMIT.

This article explains what those trials measured, what they found, and what the results mean for people considering GLP-1 therapy.

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What Is Heart Failure with Preserved Ejection Fraction?

Most people picture heart failure as a weak, struggling heart that cannot pump blood effectively. That description fits heart failure with reduced ejection fraction (HFrEF), where the left ventricle loses its pumping strength. HFpEF is different: the ejection fraction, the percentage of blood pumped with each heartbeat, is preserved at 50% or higher. The problem is stiffness, not weakness.

In HFpEF, the left ventricle cannot relax properly between beats. It becomes rigid and less able to fill with blood. Pressure builds inside the heart, backs up into the lungs, and produces the hallmark symptoms: shortness of breath with activity, fatigue, and fluid retention in the legs.

Obesity accelerates this stiffening through several pathways. Excess visceral fat increases circulating inflammatory markers that promote cardiac fibrosis. Fat deposited directly around and within the heart (pericardial and myocardial fat) compresses and stiffens the ventricle. And the sheer metabolic demand of carrying excess weight forces the heart to work harder under already-compromised filling conditions.

Because HFpEF is closely tied to metabolic health, researchers hypothesized that GLP-1 receptor agonists, with their powerful effects on weight and inflammation, could help. The clinical trials tested that hypothesis directly.

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The STEP-HFpEF Trials: Semaglutide in Heart Failure

The Primary Trial

The STEP-HFpEF trial, published in the *New England Journal of Medicine* in September 2023 (PMID 37622681, Kosiborod et al.), enrolled 529 adults with obesity (body mass index of 30 or higher) and confirmed HFpEF (ejection fraction of 45% or higher). Participants did not have type 2 diabetes. They were randomized to receive subcutaneous semaglutide 2.4 mg weekly or placebo for 52 weeks.

The trial used two coprimary endpoints chosen to reflect what patients actually experience:

• Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS): a validated patient-reported measure of heart failure symptoms and quality of life, scored from 0 to 100 (higher is better).
• Six-minute walk test distance (6MWT): a functional measure of exercise capacity.

The results were striking. Participants receiving semaglutide improved their KCCQ-CSS by an average of 16.6 points, compared to 8.7 points in the placebo group. That 7.8-point difference is clinically meaningful: in heart failure research, a 5-point improvement on the KCCQ is considered the minimum threshold for a noticeable change in how a patient feels.

The six-minute walk distance improved by 21.5 meters with semaglutide versus 1.2 meters with placebo, a 20.3-meter difference that, again, crossed accepted thresholds for clinical significance. Body weight fell by an average of 13.3% in the semaglutide group, compared to 2.6% in the placebo group. C-reactive protein (CRP), a marker of systemic inflammation, also declined significantly in the semaglutide arm, suggesting the benefit extended beyond weight alone.

The Diabetes Cohort: STEP-HFpEF DM

Because the primary trial excluded people with diabetes, a parallel study tested the same design in a different population. Published in the *Lancet* in April 2024 (PMID 38599221, Butler et al.), this trial enrolled 616 adults with HFpEF, obesity, and type 2 diabetes.

Patients with diabetes typically lose less weight on GLP-1 therapy than those without it, and that pattern held here. Body weight fell by 9.8% with semaglutide versus 3.7% with placebo. Even with smaller weight changes, the KCCQ-CSS and six-minute walk test both improved significantly in the semaglutide group. The magnitude of benefit was somewhat attenuated compared to the non-diabetes trial, but clinically meaningful results were still observed.

Extending the Data: HFmrEF Patients

A third analysis published in the *Lancet* in September 2024 (PMID 39222642, Kosiborod et al.) examined semaglutide in patients with heart failure and mildly reduced ejection fraction (HFmrEF, defined as ejection fraction between 41-49%). This group shares many features with HFpEF and historically has been underrepresented in clinical trials. The findings in this extended population were consistent with those seen in the preserved ejection fraction group.

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The SUMMIT Trial: Tirzepatide in Heart Failure

Semaglutide was not the only GLP-1 medication studied in HFpEF. The SUMMIT trial, published in the *New England Journal of Medicine* in January 2025 (PMID 39555826, Packer et al.), examined tirzepatide in 731 adults with obesity and HFpEF.

Unlike STEP-HFpEF, which used symptom scores and walk distance as primary endpoints, SUMMIT used a harder clinical outcome: the time to first occurrence of either cardiovascular death or a worsening heart failure event (defined as an unplanned hospitalization, urgent outpatient visit for heart failure, or need for intensified diuretic therapy).

Tirzepatide reduced this composite endpoint by 38% compared to placebo (hazard ratio 0.62). This is the kind of event-driven outcome cardiologists find most compelling because it reflects actual clinical deterioration and healthcare utilization, not just how a patient says they feel.

The symptom-based outcomes were also impressive. KCCQ-CSS improved by 19.5 points with tirzepatide versus 6.9 points with placebo. The six-minute walk test improved by 20.1 meters with tirzepatide versus a slight decline in the placebo group. Body weight fell by approximately 15.7% with tirzepatide versus 2.2% with placebo.

A secondary analysis of the SUMMIT trial data, published in the *Journal of the American College of Cardiology* in February 2025 (PMID 39566869, Kramer et al.), found that tirzepatide also reduced left ventricular mass and paracardiac adipose tissue on cardiac imaging. These structural changes suggest that the drug's cardiac benefits involve more than weight loss: it appears to reduce fat deposited directly around and within the heart.

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How GLP-1 Medications May Help the Heart

Several mechanisms explain why GLP-1 receptor agonists benefit HFpEF patients. Understanding them helps clarify why the effects seen in trials are biologically plausible, not coincidental.

Weight Loss Reduces Cardiac Strain

Every pound of excess weight increases the demands placed on the heart and raises the pressure inside cardiac chambers. In HFpEF, where the heart already struggles with stiffness and elevated filling pressures, even modest weight loss can produce measurable improvements in symptoms. The 10-15% body weight reductions seen in these trials represent a substantial reduction in the mechanical burden on the heart.

Reduction in Pericardial and Myocardial Fat

Visceral fat, including fat deposited around the heart (pericardial fat) and within the heart muscle itself (myocardial fat), has direct effects on cardiac function. This fat is metabolically active, secreting inflammatory cytokines and promoting fibrosis. A review published in *ESC Heart Failure* (PMID 38093506, Cimino et al.) examined the mechanistic relationship between obesity, HFpEF, and GLP-1 receptor activity, highlighting the importance of this pericardial fat reduction. The SUMMIT sub-study confirmed that tirzepatide measurably reduced paracardiac adipose tissue on imaging.

Systemic Anti-Inflammatory Effects

Both semaglutide and tirzepatide produced significant reductions in CRP in their respective trials. Chronic low-grade inflammation contributes to the myocardial fibrosis and stiffness that characterizes HFpEF. Reducing inflammatory burden may slow or partially reverse the structural processes underlying the condition.

Direct GLP-1 Receptor Activity in Cardiac Tissue

GLP-1 receptors are expressed in the heart, including in the sinoatrial node, atria, and ventricles. Animal studies suggest that GLP-1 receptor activation in cardiac tissue may have direct natriuretic effects (promoting sodium and fluid excretion), improve cardiomyocyte energy metabolism, and reduce oxidative stress. Whether these direct effects contribute meaningfully to the outcomes seen in human trials remains an active area of research.

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What This Means for People Considering GLP-1 Medications

The STEP-HFpEF and SUMMIT data are generating serious interest across cardiology and obesity medicine. But it is important to put them in proper context for patients.

GLP-1 medications are not FDA-approved to treat heart failure. The indications for semaglutide (Wegovy, Ozempic) and tirzepatide (Mounjaro, Zepbound) are weight management and type 2 diabetes. While the SELECT trial demonstrated cardiovascular outcome benefits for semaglutide in patients with obesity and established cardiovascular disease, no GLP-1 medication carries an FDA approval specifically for HFpEF treatment.

Compounded semaglutide and tirzepatide are not FDA-approved medications. The trials reviewed here used FDA-approved branded formulations at specific doses. Compounded medications are prepared by individual pharmacies based on patient-specific prescriptions, and the clinical outcomes from branded drug trials cannot be directly extrapolated to compounded products.

These findings are most relevant for patients who have both obesity and HFpEF. The trial populations were specifically selected for the combination of obesity (BMI 30+) and confirmed HFpEF. Patients with different types of heart failure or who do not meet these criteria should not assume the same benefits would apply to them.

Cardiac patients should involve their cardiologist in any treatment decision involving GLP-1 medications. Heart failure management is complex, and any new medication must be evaluated in the context of existing heart medications, kidney function, blood pressure, and overall cardiac status. GLP-1 medications can cause mild heart rate increases and, in some patients, may interact with diuretic regimens already in place for fluid management.

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What We Do Not Yet Know

The STEP-HFpEF and SUMMIT trials represent a significant advance, but important questions remain unanswered:

• Long-term durability: Both trials ran for 52 weeks. Whether the symptom improvements and (in SUMMIT's case) hard outcome reductions persist with longer use is unknown.
• What happens when the medication is stopped: Weight regain after stopping GLP-1 therapy is well-documented. Whether cardiac benefits reverse with weight regain, and at what rate, has not been studied specifically in HFpEF populations.
• Generalizability: The trial populations were carefully selected. People with severe kidney disease, recent heart failure hospitalizations, or very low ejection fractions were excluded. Real-world HFpEF patients are often more medically complex.
• Comparison with other therapies: GLP-1 medications in HFpEF have not been directly compared to SGLT2 inhibitors, which also have an evidence base in this condition. How to sequence or combine these treatments is an open question.

The ongoing STEP-HFpEF extended follow-up and additional mechanistic studies should help clarify several of these unknowns.

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Ready to Explore Your Options?

GLP-1 medications are transforming what is possible in weight management, and the emerging evidence in cardiovascular conditions like HFpEF adds another dimension to why this class of medication is drawing such attention. If you are carrying excess weight and concerned about your heart health, speaking with a licensed healthcare provider is the right first step.

Check your eligibility to learn whether a Prescriva program might be appropriate for your situation. Our licensed providers review your complete health history and coordinate with your existing care team.

*This is not medical advice. Compounded semaglutide and tirzepatide are not FDA-approved. Clinical outcomes described in this article were observed in studies of FDA-approved branded medications conducted under specific trial conditions. Consult your healthcare provider and cardiologist before making any treatment decisions. Blue Oak Services LLC dba Prescriva is a management services organization and does not practice medicine.*

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Sources

1. Kosiborod MN, et al. Semaglutide in Patients with Heart Failure with Preserved Ejection Fraction and Obesity. *N Engl J Med.* 2023;389(12):1069-1084. PMID 37622681.

1. Butler J, et al. Semaglutide versus placebo in people with obesity-related heart failure with preserved ejection fraction. *Lancet.* 2024;403(10437):1635-1648. PMID 38599221.

1. Kosiborod MN, et al. Semaglutide versus placebo in patients with heart failure and mildly reduced or preserved ejection fraction. *Lancet.* 2024;404(10457):1012-1020. PMID 39222642.

1. Packer M, et al. Tirzepatide for Heart Failure with Preserved Ejection Fraction and Obesity. *N Engl J Med.* 2025;392(5):427-437. PMID 39555826.

1. Cimino G, et al. Obesity, heart failure with preserved ejection fraction, and the role of glucagon-like peptide-1 receptor agonists. *ESC Heart Fail.* 2024;11(2):706-718. PMID 38093506.